I want to go back a second to the end of last time because in the closing moments there, we, or at least I, got a little bit lost, and where the plusses and minuses were at a certain table.

And, I want to go back and make sure we've got that straight.

We were talking about a situation where we were trying to use genetics, and the phenotypes that might be observed in mutants to try to understand the biochemical pathway because we're beginning to try to unite the geneticist's point of view who looks only at mutants, and the biochemist's point of view who looks at pathways and proteins.

And, I had hypothesized that there was some biochemists who had thought up a possible pathway for the synthesis of arginine that involved some precursor, alpha, beta, gamma, where alpha is turned into beta; beta is turned into gamma; and gamma is used to turn into arginine. And, hypothetically, there would be some enzymes: enzyme A that converts alpha, enzyme B that converts beta, and enzyme C that converts gamma.

And, we were just thinking about, what would the phenotypes look like of different arginine auxotrophs that had blocks at different stages in the pathway. If I had an arginine auxotroph that had a block here because let's say a mutation in a gene affecting this enzyme, or at a block here at a mutation affecting, say, the gene that encodes enzyme C, how would I be able to tell very simply that they were in different genes? Last time, we found that we could tell they were in different genes by doing a cross between a mutant that had the first mutation, and a mutant that had the second mutation, and looking at the double heterozygote, right? And, if in the double heterozygote you had a wild type or a normal phenotype, then they had to be in different genes, OK? Remember that?

That was called a test of complementation.

That was how we were able to sort out which mutations were in the same gene, and which mutations were in different genes.

Now we can go a step further. When we've established that they're in different genes, we can try to begin to think, how do these genes relate to a biochemical pathway?

I wanted to begin to introduce, because it'll be relevant for today, this notion: so, suppose I had a mutation that affected enzyme A so that this enzymatic step couldn't be carried out.

Such a mutant, when I just try to grow it on minimal medium won't be able to grow. If I give it the substrate alpha, it doesn't do it any good because it hasn't got the enzyme to convert alpha. So, given alpha, it won't grow. But if I give it beta, what will happen? It can grow because I've bypassed the defect. What about if I give it gamma? Arginine?

Now, if instead the mutation were affecting enzymatic step here, then if I give it on minimal or medium but it can grow on gamma. What about this last line?

If I have a mutation and the last enzymatic step, minimal medium can't grow with alpha, can't grow with beta, can't even grow with gamma. But, it can grow with arginine because I've bypassed that step. So, I get a different phenotype, the inability to grow even on gamma, but I can grow on arginine. Now, here, if I put together those mutants and make a double mutant, a double homozygote, let's say, that's defective in both A and B, which will it look like? Will it be able to grow on minimal medium? Will it be able to grow on alpha?

Will it be able to grow on beta?

Will it be able to grow on gamma and arginine? What about if I have a double mutant in B and C, minus, minus, minus, minus, plus? So this looks the same as that. This looks the same as that.

And so, by looking at different mutant combinations, I can see that the phenotype of B here is what occurs in the double mutant. So, this phenotype is epistatic to this phenotype.

Epistatic means stands upon, OK? So, phenotypes, just like phenotypes can be recessive or dominant, you can also speak about them being epistatic. And epistatic means when you have both of two mutations together at the epistatic then one of them is epistatic to the other, perhaps.

It will, in fact, be the one that is present.

So, this is not so easy to do in many cases because if I take different kinds of mutation affecting wing development, and I put them together in the same fly, I may just get a very messed up wing, and it's very hard to tell that the double mutant has a phenotype that looks like either of the two single mutants.

But sometimes, if they fall very nicely in a pathway where this affects the first step, this affects the second step this affects the third step, this affects the fourth step, then the double mutant will look like one of those, OK? And, that way you can somehow order things in a biochemical pathway. Now, notice, this is all indirect, right? This is what geneticists did in the middle of the 20th century to try to figure out how to connect up mutants to biochemistry.

Actually, that's not true. It's what geneticists still do today because you might think that Well, we don't need to do this anymore, but in fact geneticists constantly are looking at mutants and making connections trying to say, what does this double combination look like? What does that double combination look like, and how does that tell us about the developmental pathway, which cell signals which cell? This turns out to be one of the most powerful ways to figure out what mutations do by saying the combination of two mutations looks like the same as one of them, allowing you to order the mutations in a pathway.

And, there's no general way to grind up a cell and order things in a pathway. Genetics is a very powerful tool for doing that.

Now, there are some ways to grind up cells and order things, but you need both of these techniques to believe stuff.

Anyway, I wanted to go over that, because it is an important concept, the concept of epistasis, the concept of relating mutations to steps and pathways, but what I mostly want to do today is go on now to talk about genetics not in organisms like yeast or fruit flies or even peas, but genetics in humans.

So, what's different about genetics in humans than genetics in yeast?

You can't choose who mates with whom. Well, you can.

I mean, in the days of arranged marriages maybe you couldn't, but you can choose who mates with whom, but only for yourself, right? What you can't do is arrange other crosses in the human population as an experimentalist. Now, your own choice of mating, unfortunately or fortunately perhaps produces too few progeny to be statistically significant. As a parent of three, I think about what it would take to raise a statistically significant number of offspring to draw any conclusions, and I don't think I could do that.

So, you're absolutely right. We can't arrange the matings that we want in the human population. So, that's the big difference.

So, can we do genetics anyway? How do we do genetics even though we can't arrange the matings the way we'd like to? Sorry?

Well, family trees. We have to take the matings as we find them in the human population. You can talk to somebody who might have an interesting phenotype, I don't know, attached earlobes, or very early heart disease, or some unusual color of eyes, and begin to collect a family history on that person.

It's a little bit of a dodgy thing because you might just be relying on that person's recollection. So, if you were really industrious about this, you'd go check out each of their family members and test for yourself whether they have the phenotype. People who do serious human genetic studies often go and do that. They have to go confirm, either by getting hospital records or interviewing the other members of the family, etc. So, this is not as easy as plating out lots of yeasts on a Petri plate.

And then you get pedigrees. And the pedigrees look like this.

Here's a pedigree. Tell me what you make of it.

Now, symbols: squares are males, circles are females by convention, a colored in symbol means the phenotype that we're interested in studying at the moment. So, in any given problem, somebody will tell you, well, we're studying some interesting phenotype. You often have an index case or a proband, meaning the person who comes to clinical attention, and then you chase back in the pedigree and try to reconstruct.

So, suppose I saw a pedigree like this.

What conclusions could I draw? Sorry? Recessive, sex link trait; why sex link trait? So, let's see if we can get your model up here. You think that this represents sex-linked inheritance. So, what would the genotype be of this male here? Mutant: I'll use M to denote a mutant carried on the X chromosome, and a Y on the opposite chromosome.

What's the genotype of the female here?

So, it's plus over plus where I'll use plus to denote the gene carried on the normal X chromosome. OK, and then what do you think happened over here? So, mutant over plus, you mate to this male who is plus over plus. Why is that male plus over plus? Oh, right, good point.

It's not plus over plus. It's plus over Y. Why is that male plus over Y as opposed to mutant over Y?

He'd have the mutant phenotype. So, he doesn't have the mutant phenotype so he can infer he's plus over Y. OK, and then what happens here? Mutant over Y; this is plus over Y. How did this person get plus over Y? They just the plus for mom, and the daughters, Y from dad, and a plus from mom. That's cool. Now, what about the daughters there? They're plus over plus, or M over plus? Is one, one, and one the other? Well, in textbooks it's always plus over plus and M over plus, but in real life? We don't know, right? So, this could be plus over plus, or M over plus, we don't know, OK? Now, what about on this side of the pedigree here?

What's the genotype here? Plus over Y, OK.

Why not mutant over Y? Because if they got the mutant, it would have to come from the, OK, so here, plus over plus, and then here, everybody is normal because there's no mutant allele segregated.

Yes? Yeah, couldn't there just be recessive? I mean, it's a nice story about the sex link but couldn't it be recessive? So, walk me through it being recessive. M over plus, plus over plus. Wait, wait, wait, hang on. Could this be M over plus, and that person be affected?

It's got to be M over M, right so mutants over mutants but that's possible. Yeah, OK. So, what would this person be? Plus over plus, let's say, come over here. Now, what would this person be? M plus. It has to be M plus because, OK, and what about this person here? M plus, now what about the offspring? So, one of them is M over M, plus over plus, and two M pluses. Does it always work out like that?

[LAUGHTER] No, it doesn't always work out like that at all.

So, I'm just going to write plus over plus here just to say, tough, right? In real life, it doesn't always come out like that.

What about over here? It would have to be plus over plus.

Why not? It doesn't because it could be M over plus and have no effect at offspring by chance, right? But, you were going to say it's plus over plus because in the textbooks it's always plus over plus in pictures like this, right? And then, it all turns out to be pluses and mutants, and pluses and mutants, and all that, right? Well, which picture's right?

Sorry? You don't know. So, that's not good. There's supposed to be answers to these things. Could either be true? Which is more likely? The one on the left? Why? More statistically probable, how come? Because it is. It may not quite suffice as a fully complete scientific answer though.

Yes? Yep. Well, but I have somebody who is affected here. So, given that I've gotten affected person in the family -- yeah, so it is actually, you're right, statistically somewhat less likely that you would have two independent M's entering the same pedigree particularly if M is relatively rare.

If M is quite common, however, suppose M were something was a 20% frequency in the population, then it actually might be quite reasonable that this could happen. So, what would you really want to do to test this? Sorry? Well, if you found any females here maybe you'd be able to conclude that it was autosomal recessive because females never show a sex-linked trait. Is that true?

No, that's not true. Why not? You're right. So, you just have to be homozygous for it on the X. So, having a single female won't, I mean, she's not going to take that as evidence. Get an affected female and demonstrate that all of her male offspring show the trait. Cross her with, wait, wait.

This is a human pedigree guys [LAUGHTER]. Whew! There are issues involved here, right? You could introduce her to a normal guy, [LAUGHTER] but whether you can cross her to a normal guy is not actually allowed. So, you see, these are exactly the issues in making sense out of pedigrees like this.

So, what you have to do is you have to collect a lot of data, and the kinds of characteristics that you look for in a pedigree, but they are statistical characteristics, and notwithstanding -- So, this could be colorblindness or something, but notwithstanding the pictures in the textbook of colorblindness and all that, you really do have to take a look at a number of properties. What are some properties?

One you've already referred to which is there's a predominance in males if it's X-linked. Why is there a predominance in males? Well, there's a predominance in males because if I have an X over Y and I've got a mutation paired on this X chromosome, males only have to get it on one.

Females have to get it on both, and therefore it's statistically more likely that males will get it. So, for example, the frequency of colorblindness amongst males is what? Yeah, it's 8-10%, something like that. I think it's about 8% or so.

And, amongst females, well, if it's 8% to get one, what's the chance you're going to get two?

It's 8% times 8% is a little less than 1% right?

It's 0.64%, OK, in females. So, we'll just go 8% squared. So in males, 8% in females, less than one percent.

So, there is a predominance in males of these sex-linked traits. Other things: affected males do not transmit the trait to the kids, in particular do not transmit it to their sons, right, because they are always sending the Y chromosomes to their songs. Carrier females transmit to half of their sons, and affected females transmit to all of their sons. And, the trait appears to skip generations, although I don't like this terminology.

It skips generations. These are the kinds of properties that you have. So, hemophilia, a good example of this, if I have a child with hemophilia, male with hemophilia, would you be surprised if his uncle had hemophilia? Which uncle would it be, maternal or paternal?

The maternal uncle would have hemophilia most likely.

It's always possible it could be paternal. This is the problem with human genetics is you've got to get enough families so the pattern becomes overwhelmingly clear, OK, because otherwise, as you can see with small numbers, it's tough to be absolutely certain.

So, these are properties of X linked traits.

How about baldness? Is baldness, that's a sex-linked trait? How come? You don't see a lot of bald females.

Does that prove it's sex linked? Sorry? Guys are stressed more.

[LAUGHTER] Is there evidence that it has anything to do with stress?

Actually, it has to do with excess testosterone it turns out, that high levels of testosterone are correlated with male pattern baldness, but does the fact that males become bald indicate that this is a sex linked trait? No. Just because it's predominant in male, we have to check these other properties.

Is it the case that bald fathers tend to have bald sons?

Any evidence on this point? Common-sensical evidence from observation? It's pretty clear. It's very clearly not a sex-linked trait. It's a sex-limited trait, because in order to show this you need to be male because the high levels of testosterone are not found in females even if they have the genotype that might predispose them to become bald if they were male. So, it actually is not a sex-linked trait at all, and it's very clear that male pattern baldness does run in families more vertically. So, you've got to be careful about the difference between sex linked and sex limited, and sex linked you can really pick out from transmission and families.

OK, here's another one. New pedigree.

She married twice here. OK, what do we got?

Yep? She married again. She married twice. She didn't have any offspring the second time. But that happens, and you have to be able to draw it in the pedigree.

She's entitled, all right. OK, so she got married again, no offspring from this marriage. That's her legal symbol. You guys think that's funny. It's real, you know?

OK, that doesn't mean she's married to two people at the same time.

This is not a temporal picture. So, what do we got here? Yep?

Sorry, of this person? Well, I'm drawing them as an empty symbol here, indicating that we do not think they have the trait.

They're not carriers. How do you propose to find that out?

Look at the children. Well, the children are affected. They could be carriers. The data are what they are.

You've got to interpret it. Does this person have to be a carrier? What kind of trait do you think this is?

Dominant? Does this look like autosomal dominant to you?

Yep? Oh, not all the kids have the trait in the first generation, and if this was dominant, they'd all have it? What's a possible genotype for this person?

Mutant over plus. And, these kids could be mutant over plus.

This could be plus over plus, and this could be plus over plus, mutant over plus, plus over plus, mutant over plus, and plus over plus would be one possibility. On average, what fraction of the kids should get the trait? About half the kids, right? So, let's see what characteristics we have here. We see the trait in every generation.

On average, half the kids get the trait.

Half of the offspring of an affected individual are affected.

What else? Males and females? Roughly equal in males and females?

Sorry? One, two, three, four, five to two. So, it's a 5:2 ratio?

Oh, in the offspring it's a 2:1 ratio. So, this is like Mendel.

You see this number and you say, OK, 2:1. Isn't that trying to tell me something? Not with six offspring. That's the problem is with six offspring, 2:1 might be trying to tell you 1:1.

And it is. If I had a dominantly inherited trait where there's a 50/50 chance of each offspring getting the disease and it was autosomal, not sex linked, there would be very good odds of getting two males and one female because it happens: flip coins and it happens. So, you have to take that into account, and here you see what else we have. Roughly equal numbers of males and females, they transmit equally, and unaffecteds never transmit.

This would be the classic autosomal dominant trait.

Right, here this mutant would go mutant over plus, mutant over plus, plus over plus, mutant over plus, plus over plus, plus over plus, and you'd see here that three out of the five here, and one, two, three out of the six there: that's a little more than half but it's small numbers here, right? This is a classic autosomal dominant as in the textbooks. Yes? Turns out not to make too much of a difference. It turns out that there's lots of genome that's on either. And so, it is true that males are more susceptible to certain genetic diseases.

So, it'll be some excess, but it won't matter for this.

Now, in real life it doesn't always work so beautifully.

We'll take an example: colon cancer. There are particular autosomal dominant mutations here that cause a high risk of colon cancer.

People who have mutations in a certain gene, MLH-1, have about a 70% risk of getting colon cancer in their life.

But notice, it's not 100%. You might have incomplete penetrance.

Incompletely penetrance means not everybody who gets the genotype gets the phenotype. Not all people with the M over plus genotype show the phenotype. Once you do that, it messes up our picture colossally, because, tell me, how do we know that this person over here is not actually M over plus.

Maybe they're cryptic. They haven't shown the phenotype.

And maybe, it'll appear in the next generation. That'll screw up everything. It screws up our rule about not transmitting through unaffected, it screws up the rule about not being shown in every generation, and it will even screw up our 50/50 ratio because if half the offspring get M over plus, but only 70% of that half show the phenotype, then only 35% of the offspring will show the phenotype. Unfortunately, this is real life.

The rest is here:

Lecture 9: Human Genetics | Video Lectures | Introduction ...

Introduction[edit]

Genetics is the science of the way traits are passed from parent to offspring. For all forms of life, continuity of the species depends upon the genetic code being passed from parent to offspring. Evolution by natural selection is dependent on traits being heritable. Genetics is very important in human physiology because all attributes of the human body are affected by a persons genetic code. It can be as simple as eye color, height, or hair color. Or it can be as complex as how well your liver processes toxins, whether you will be prone to heart disease or breast cancer, and whether you will be color blind. Defects in the genetic code can be tragic. For example: Down Syndrome, Turner Syndrome, and Klinefelter's Syndrome are diseases caused by chromosomal abnormalities. Cystic fibrosis is caused by a single change in the genetic sequence.

Genetic inheritance begins at the time of conception. You inherited 23 chromosomes from your mother and 23 from your father. Together they form 22 pairs of autosomal chromosomes and a pair of sex chromosomes (either XX if you are female, or XY if you are male). Homologous chromosomes have the same genes in the same positions, but may have different alleles (varieties) of those genes. There can be many alleles of a gene within a population, but an individual within that population only has two copies, and can be homozygous (both copies the same) or heterozygous (the two copies are different) for any given gene.

Genetics is important to medicine. As more is understood about how genetics affects certain defects and diseases, cures and treatments can be more readily developed for these disorders. The sequence of the human genome (approximately 3 billion base pairs in a human haploid genome with an estimated 20,000-25,000 protein-coding genes) was completed in 2003, but we are far from understanding the functions and regulations of all the genes. In some ways medicine is moving from diagnosis based on symptoms towards diagnosis based on genetics, and we are moving into what many are calling the age of personalized medicine.

Deoxyribonucleic acid (DNA) is the macromolecule that stores the information necessary to build structual and functional cellular components. It also provides the basis for inheritance when DNA is passed from parent to offspring. The union of these concepts about DNA allows us to devise a working definition of a gene. A gene is a segment of DNA that codes for the synthesis of a protein and acts as a unit of inheritance that can be transmitted from generation to generation. The external appearance (phenotype) of an organism is determined to a large extent by the genes it inherits (genotype). Thus, one can begin to see how variation at the DNA level can cause variation at the level of the entire organism. These concepts form the basis of genetics and evolutionary theory.

rotating animation of a DNA molecule.

A gene is made up of short sections of DNA which are contained on a chromosome within the nucleus of a cell. Genes control the development and function of all organs and all working systems in the body. A gene has a certain influence on how the cell works; the same gene in many different cells determines a certain physical or biochemical feature of the whole body (e.g. eye color or reproductive functions). All human cells hold approximately 30,000 different genes. Even though each cell has identical copies of all of the same genes, different cells express or repress different genes. This is what accounts for the differences between, let's say, a liver cell and a brain cell . Genotype is the actual pair of genes that a person has for a trait of interest. For example, a woman could be a carrier for hemophilia by having one normal copy of the gene for a particular clotting protein and one defective copy. A Phenotype is the organisms physical appearance as it relates to a certain trait. In the case of the woman carrier, her phenotype is normal (because the normal copy of the gene is dominant to the defective copy). The phenotype can be for any measurable trait, such as eye color, finger length, height, physiological traits like the ability to pump calcium ions from mucosal cells, behavioral traits like smiles, and biochemical traits like blood types and cholesterol levels. Genotype cannot always be predicted by phenotype (we would not know the woman was a carrier of hemophilia just based on her appearance), but can be determined through pedigree charts or direct genetic testing. Even though genotype is a strong predictor of phenotype, environmental factors can also play a strong role in determining phenotype. Identical twins, for example, are genetic clones resulting from the early splitting of an embryo, but they can be quite different in personality, body mass, and even fingerprints.

Genetics (from the Greek genno = give birth) is the science of genes, heredity, and the variation of organisms. The word "genetics" was first suggested to describe the study of inheritance and the science of variation by prominent British scientist William Bateson in a personal letter to Adam Sedgwick, dated April 18, 1905. Bateson first used the term "genetics" publicly at the Third International Conference on Genetics (London, England) in 1906.

Heredity and variations form the basis of genetics. Humans apply knowledge of genetics in prehistory with the domestication and breeding of plants and animals. In modern research, genetics provide important tools for the investigation of the function of a particular gene, e.g., analysis of genetic interactions. Within organisms, genetic information is generally carried in chromosomes, where it is represented in the chemical structure of particular DNA molecules.

Genes encode the information necessary for synthesizing the amino-acid sequences in proteins, which in turn play a large role in determining the final phenotype, or physical appearance of the organism. In diploid organisms, a dominant allele on one chromosome will mask the expression of a recessive allele on the other. While most genes are dominant/recessive, others may be codominant or show different patterns of expression. The phrase "to code for" is often used to mean a gene contains the instructions about a particular protein, (as in the gene codes for the protein). The "one gene, one protein" concept is now known to be the simplistic. For example, a single gene may produce multiple products, depending on how its transcription is regulated. Genes code for the nucleotide sequence in mRNA and rRNA, required for protein synthesis.

Gregor Mendel researched principals of heredity in plants. He soon realized that these principals also apply to people and animals and are the same for all living animals.

Gregor Mendel experimented with common pea plants. Over generations of the pea plants, he noticed that certain traits can show up in offspring with out blending any of the parent's characteristics. This is a very important observation because at this point the theory was that inherited traits blend from one generation to another.

Pea plant reproduction is easily manipulated. They have both male and female parts and can easily be grown in large numbers. For this reason, pea plants can either self-pollinate or cross-pollinate with other pea plants.

In cross pollinating two true-breeding plants, for example one that came from a long line of yellow peas and the other that came from a long line of green peas, the first generation of offspring always came out with all yellow peas. The following generations had a ratio of 3:1 yellow to green. In this and in all of the other pea plant traits Mendel observed, one form was dominant over another so it masked the presence of the other allele. Even if the phenotype (presence) is covered up, the genotype (allele) can be passed on to other generations.

Time line of notable discoveries

1859 Charles Darwin publishes "The Origin of Species"

1865 Gregor Mendel's paper, Experiments on Plant Hybridization

1903 Chromosomes are discovered to be hereditary units

1906 The term "genetics" is first introduced publicly by the British biologist William Bateson at the Third International Conference on Genetics in London, England

1910 Thomas Hunt Morgan shows that genes reside on chromosomes, and discovered linked genes on chromosomes that do NOT follow Mendel's law of independent allele segregation

1913 Alfred Sturtevant makes the first genetic map of a chromosome

1913 Gene maps show chromosomes contain linear arranged genes

1918 Ronald Fisher publishes On the correlation between relatives on the supposition of Mendelian inheritance - the modern synthesis starts.

1927 Physical changes in genes are called mutations

1928 Fredrick Griffith discovers a hereditary molecule that is transmissible between bacteria

1931 Crossing over is the cause of recombination

1941 Edward Lawrie Tatum and George Wells Beadle show that genes code for proteins

1944 Oswald Theodore Avery, Colin McLeod and Maclyn McCarty isolate DNA as the genetic material (at that time called transforming principle)

1950 Erwin Chargaff shows that the four nucleotides are not present in nucleic acid in stable proportions, but that some general rules appear to hold. (e.g., the nucleotide bases Adenine-Thymine and Cytosine-guanine always remain in equal proportions)

1950 Barbra McClintock discovers transposons in maize

1952 The Hershey-Chase experiment proves the genetic information of phages (and all other organisms) to be DNA

1953 DNA structure is resolved to be a double helix by James D. Watson and Francis Crick, with help from Rosalind Franklin

1956 Jo Hin Tjio and Albert Levan established the correct chromosome number in humans to be 46

1958 The Meselson-Stahl experiment demonstrates that DNA is semi-conservatively replicated

1961 The genetic code is arranged in triplets

1964 Howard Temin showed using RNA viruses that Watson's central dogma is not always true

1970 Restriction enzymes were discovered in studies of a bacterium Haemophilus influenzae, enabling scientists to cut and paste DNA

1977 DNA is sequenced for the first time by Fred Sangr, Walter Gilbert, and Allan Maxam working independently. Sanger's lab complete the entire genome of sequence of Bacteriophage

1983 Kary Banks Mullis discovers the polymerase chain reaction (PCR) enabling the easy amplification of DNA

1985 Alec Jeffreys discovers genetic finger printing

1989 The first human gene is sequenced by Francis Collin and Lap-Chee Tsui. It encodes the CFTR protein. Defect in this gene causes Cystic Fibrosis

1995 The genome of Haemophilus influenza is the first genome of a free living organism to be sequenced.

1996 Saccharomyces cerevisiae is the first eukaryote genome sequence to be released.

1998 The first genome sequence for a multicellular eukaryote, C. elegans is released.

2001 First draft sequences of the human genome are released simultaneously by the Human Genome Project and Celera Genomic

2003 (14 April) Successful completion of Human Genome Project with 99% of the genome sequenced to a 99.99% accuracy

2006 Marcus Pembrey and Olov Bygren publish Sex-specifics, male line trans-generational responses in humans, a proof of epigenetics

Transcription is the process of making RNA. In response to an enzyme RNA polymerase breaks the hydrogen bonds of the gene. A gene is a segment of DNA which contains the information for making a protein. As it breaks the hydrogen bonds it begins to move down the gene. Next the RNA polymerase will line up the nucleotides so they are complementary. Some types of RNA will leave the nucleus and perform a specific function.

Translation is the synthesis of the protein on the ribosome as the mRNA moves across the ribosome. There are eleven basic steps to translation.

1. The mRNA base sequence determines the order of assembling of the amino acids to form specific proteins.

2. Transcription occurs in the nucleus, and once you have completed transcription the mRNA will leave the nuecleus, and go into the cytoplasm where the mRNA will bind to a free floating ribosome, where it will attach to a small ribosomal subunit.

3. Methionine-tRNA binds to the nucleotides AUG. AUG is known as the start codon and is found at the beginning of each mRNA.

4. The complex then binds to a large ribosomal subunit. Methionine-tRNA is bound to the P site of the ribosome.

5. Another tRNA containing a second amino acid (lysine) binds to the second amino acid. Binding to the second condon of mRNA (on the A-site of the ribosome).

6. Peptidyl transferase, forms a peptide3 bond between the two amino acids (methionine and lysine)

7. The first amino tRNA is released and mRNA is translocated one codon carrying the second tRNA (still carrying the two amino acids) to the P site.

8. Another tRNA with attached amino acid (glutamine) moves into the A site and binds to that codon.

9. It will now form a peptide bond with lysine and glutamine

10. Now the tRNA in the P site will be let go, and mRNA is translocated one codon, (the tRNA with three amino acids) to the P site.

11. This will continue going until it reaches the stop codon (UAG) on the mRNA. Then this codon will tell it to release the polypeptide chain.

These are some good sites to visit

Select A the video of the Inner Life of a Cell. If you want to hear the descriptions in this process go to B web site and select the Inner Life: view the animation.

Children inherit traits, disorders, and characteristics from their parents. Children tend to resemble their parents especially in physical appearance. However they may also have the same mannerisms, personality, and a lot of the time the same mental abilities or disabilities. Many negatives and positives tend to "run in the family". A lot of the time people will use the excuse "It runs in the family" for things that have alternative reasons, such as a whole family may be overweight, yes it may "run in the family" but it could also be because of all the hamburgers and extra mayo that they all eat. Or the fact that after they eat the hamburgers they all sit on the couch and don't move for the rest of the evening. Children may have the same habits (good or bad) as their parents, like biting their nails or enjoying reading books. These things aren't inherited they are happening because children imitate their parents, they want to be like mom or dad. Good examples are just as important as good genes.

A person's cells hold the exact genes that originated from the sperm and egg of his parents at the time of conception. The genes of a cell are formed into long strands of DNA. Most of the genes that control characteristic are in pairs, one gene from mom and one gene from dad. Everybody has 22 pairs of chromosomes (autosomes) and two more genes called sex-linked chromosomes. Females have two X (XX) chromosomes and males have an X and a Y (XY) chromosome. Inherited traits and disorders can be divided into three categories: unifactorial inheritance, sex-linked inheritance, and multifactor inheritance.

Traits such as blood type, eye color, hair color, and taste are each thought to be controlled by a single pair of genes. The Austrian monk Gregor Mendel was the first to discover this phenomenon, and it is now referred to as the laws of Mendelian inheritance. The genes deciding a single trait may have several forms (alleles). For example, the gene responsible for hair color has two main alleles: red and brown. The four possibilities are thus

Brown/red, which would result in brown hair, Red/red, resulting in red hair, Brown/brown, resulting in brown hair, or Red/brown, resulting in red hair.

The genetic codes for red and brown can be either dominant or recessive. In any case, the dominant gene overrides the recessive.

When two people create a child, they each supply their own set of genes. In simplistic cases, such as the red/brown hair, each parent supplies one "code", contributing to the child's hair color. For example, if dad has brown/red he has a 50% chance of passing brown hair to his child and a 50% of passing red hair. When combined with a mom who has brown/brown (who would supply 100% brown), the child has a 75% chance of having brown hair and a 25% chance of having red hair. Similar rules apply to different traits and characteristics, though they are usually far more complex.

Some traits are found to be determined by genes and environmental effects. Height for example seems to be controlled by multiple genes, some are "tall" genes and some are "short" genes. A child may inherit all the "tall" genes from both parents and will end up taller than both parents. Or the child my inherit all the "short" genes and be the shortest in the family. More often than not the child inherits both "tall" and "short" genes and ends up about the same height as the rest of the family. Good diet and exercise can help a person with "short" genes end up attaining an average height. Babies born with drug addiction or alcohol addiction are a sad example of environmental inheritance. When mom is doing drugs or drinking, everything that she takes the baby takes. These babies often have developmental problems and learning disabilities. A baby born with Fetal alcohol syndrome is usually abnormally short, has small eyes and a small jaw, may have heart defects, a cleft lip and palate, may suck poorly, sleep poorly, and be irritable. About one fifth of the babies born with fetal alcohol syndrome die within the first weeks of life, those that live are often mentally and physically handicapped.

Sex-linked inheritance is quite obvious, it determines your gender. Male gender is caused by the Y chromosome which is only found in males and is inherited from their fathers. The genes on the Y chromosomes direct the development of the male sex organs. The x chromosome is not as closely related to the female sex because it is contained in both males and females. Males have a single X and females have double XX. The X chromosome is to regulate regular development and it seems that the Y is added just for the male genitalia. When there is a default with the X chromosomes in males it is almost always persistent because there is not the extra X chromosome that females have to counteract the problem. Certain traits like colorblindness and hemophilia are on alleles carried on the X chromosome. For example if a woman is colorblind all of her sons will be colorblind. Whereas all of her daughters will be carriers for colorblindness.

Our knowledge of the mechanisms of genetic inheritance has grown a lot since Mendel's time. It is now understood, that if you inherit one allele, it can sometimes increase the chance of inheriting another and can affect when or how a trait is expressed in an individuals phenotype. There are levels of dominance and recessiveness with some traits. Mendel's simple rules of inheritance does not always apply in these exceptions.

Polygenic traits are traits determined by the combined effect of more than one pair of genes. Human stature is an example of this trait. The size of all body parts from head to foot combined determines height. The size of each individual body part are determined by numerous genes. Human skin, eyes, and hair are also polygenic genes because they are determined by more than one allele at a different location.

When there is incomplete dominance, blending can occur resulting in heterozygous individuals. An example of intermediate expression is the pitch of a human male voice. Homozygous men have the lowest and highest voice for this trait (AA and aa). The child killer Tay- Sachs is also characterized by incomplete dominance.

For some traits, two alleles can be co-dominant. Were both alleles are expressed in heterozygous individuals. An example of that would be a person with AB blood. These people have the characteristics of both A and B blood types when tested.

There are some traits that are controlled by far more alleles. For example, the human HLA system, which is responsible for accepting or rejecting foreign tissue in our bodies, can have as many as 30,000,000 different genotypes! The HLA system is what causes the rejection of organ transplants. The multiple allele series is very common, as geneticists learn more about genetics, they realize that it is more common than the simple two allele ones.

Modifying and regulator genes are the two classes of genes that may have an effect on how the other genes function. Modifying Genes alter how other genes are expressed in the phenotype. For example, a dominant cataracts gene may impair vision at various degrees, depending on the presence of a specific allele for a companion modifying gene. However, cataracts can also come from excessive exposure to ultraviolet rays and diabetes. Regulator Genes also known as homoerotic genes, can either initiate or block the expression of other genes. They also control a variety of chemicals in plants and animals. For example, Regulator genes control the time of production of certain proteins that will be new structural parts of our bodies. Regulator genes also work as a master switch starting the development of our body parts right after conception and are also responsible for the changes in our bodies as we get older. They control the aging processes and maturation.

Some genes are incomplete penetrate. Which means, unless some environmental factors are present, the effect does not occur. For example, you can inherit the gene for diabetes, but never get the disease, unless you were greatly stressed, extremely overweight, or didn't get enough sleep at night.

Some of the most common inherited diseases are hemochromatosis, cystic fibrosis, sickle cell anemia and hemophilia. They are all passed along from the parents and even if the parents don't show signs of the disease they may be carriers which mean that all of the children they have may be born with the disease. There is genetic testing that may be done prenatally to determine if the baby is conflicted with one of these diseases.

Even though most people have never heard of hemochromatosis it is the most common inherited disease. About 1 in 300 are born with hemochromatis and 1 in 9 are carriers. The main characteristic is the intake of too much iron into the inflicted body. Iron is crucial to the workings of hemoglobin but too much iron is just as bad as too little iron. With hemochromatosis deposits of iron form on almost every major organ especially the liver, heart and pancreas, which causes complete organ failure. Hemochromatosis patients usually absorb two or three times the iron that is needed for normal people. Hemochromatosis was first discovered in 1865 and most patients have Celtic ancestry dating back 60 or 70 generations.

The most common treatment for hemochromatosis is to induce anemia and maintain it until the iron storage is reduced. This is done by therapeutic phlebotomy. Phlebotomy is the removal of a unit of blood (about 500 mls.) This must be done one to two times a week and can take weeks, months, or years to complete. After this treatment some patients will never have to do it again and others will have to do it many times over the course of their life. Patients who undergo their recommended treatments usually go on to live a long and healthy life. Patients who decide against treatment increase their chances of problems such as organ failure -- or even death. Along with phlebotomy treatment, patients should stick to a low iron diet and should not cook with iron cookware.

Cystic fibrosis is a disease that causes thick, sticky mucus to build up in the lungs and digestive tract. It is the most common lung disease in children and young adults and may cause early death. The mucus builds up in the breathing passages of the lungs and in the pancreas. The build up of the mucus results in terrible lung infections and digestion problems. Cystic fibrosis may also cause problem with the sweat gland and a man's reproductive system. There are more than 1,000 mutations of the CF gene, symptoms vary from person to person. The most common symptoms are: No bowel movements for the first 24 to 48 hours of life, stools that are pale or clay colored, foul smelling or that float, infants that have salty-tasting skin, recurrent respiratory infections like pneumonia, coughing or wheezing, weight loss or low weight gain in childhood, diarrhea, delayed growth, and excessive fatigue. Most patients are diagnosed by their first birthday but less severe cases sometimes aren't caught until after 18 years of age. 40% of patients are over 18 years old and the average life span of CF patients is about 35 years old, which is a huge increase over the last 30 years. Patients usually die of lung complications.

In 2005 the U.S food and drug administration approved the first DNA based blood test to help detect CF. Other tests to help detect CF include: Sweat chloride test, which is the standard test for CF. High salt levels in the patients sweat is an indication of CF, Fecal fat test, upper GI and small bowel series, and measurements of pancreatic function. After a diagnosis has been made there are a number of treatments available, these include: Antibiotics for respiratory infections, pancreatic enzyme replacement, vitamin supplements (mostly A, D, E, and K), inhalers to open the airways, enzyme replacement therapy which makes it easier to cough up the mucus, pain relievers, and in very severe cases, lung transplants.

Sickle cell anemia is an inherited disease of the red blood cells which causes abnormally shaped red cells. A typical red blood cell has about 270 million hemoglobin molecules, which bind with oxygen. In a person with sickle cell disease, one amino acid is changed in the hemoglobin molecule, and the end result is misshapen red blood cells. In a patient with sickle cell disease the red blood cells change from the normal round shape to the shape of a sickle or "C" shaped. The abnormal shape causes the cells to get stuck in some blood vessels which causes blockage in the vessel. This causes pain and can destroy organs because of the lack of oxygen. Sickle cells live only 10 to 20 days and a normal cell lives about 120 days.

Red blood cells with sickle-cell mutations.

This rapid death of blood cells leads to chronic anemia. Complications can include severe pain, terrible infection, swelling of the feet and hands, stroke, damage to the eyes, and damaged body organs. These effects can vary from person to person depending on the type of sickle cell disease they have. Some patients are mostly healthy and others are in the hospital more than they are out. Thanks to diagnosis and treatment advancements, most children born with sickle cell grow up to have a normal and relatively healthy life. The form of sickle cell is determined by which genes they inherit from the parents. When a child inherits a sickle cell gene (hemoglobin gene) from each parent it is called hemoglobin SS disease ( which is the formal name for sickle cell). When a child inherits a sickle cell gene from one parent and a different abnormal gene from the other parent, it is a form of disease called hemoglobin SC disease or hemoglobin S-thalassemia. If a child inherits a normal gene from one parent and a sickle cell gene from the other, the child will not have sickle cell but will be a carrier and may pass it to their children. Sickle cell affects mostly African Americans and some Latino Americans. A person who is a carrier (has one copy of the gene) is resistant to malaria. This heterozygote advantage explains why the gene is more common in people in equatorial regions, or who are descendants of such people (such as African Americans).

Sickle cell is diagnosed at birth with a simple blood test. If the first blood test is positive then a second test is done just for confirmation. Because of the high risk of infections that occur with sickle cell, early diagnosis is very important. Other than a bone marrow transplant there is no known cure for sickle cell. Bone marrow transplants have a high risk of rejection and aren't an available option for every patient. The patient would need a bone marrow donor match with a low risk of rejection. Even without a cure, with the use of pain medications and antibiotic treatments, children with sickle cell can live a long and happy life. Blood transfusions are sometimes used to treat episodes of severe pain. For adults who have recurrent pain episodes (at least 3 yearly), a cancer drug, hydroxyurea (marketed as Droxia), has been approved to relieve symptoms. It appears to work by increasing the flexibility of sickle cells.

About two thirds of people who have Hemophilia have inherited it. For the other third, there is no known cause for possessing the disorder. There are two types of hemophilia, Type A and Type B. Both are caused by a low level or a complete absence of protein in the blood. Without this protein, blood is not able to clot.

Some of the symptoms of Hemophilia are bleeding in the joints, knees, and ankles. Stiffness without pain in the joints, stiffness with a lot of warmth,(most ability for movement is lost due to swelling) blood in the urine or stool, excessive bleeding after surgery or loosing a tooth, excessive bruising, abnormal menstrual bleeding, and nose bleeds that last for long periods of time.

Hemophiliacs blood does not coagulate like a normal persons. Coagulation controls bleeding, it changes blood from a liquid to a solid. Within seconds of a cut or scrape, platelets, calcium and other tissue factors start working together to form a clot. Over a short time the clot strengthens and then dissolves as the injury heals. Hemophiliacs are missing the clotting factor, or it isn't working correctly which causes them to bleed for a longer time. The most common myth is that a person with a bleeding disorder will bleed to death from a minor wound or that their blood flows faster than somebody without a bleeding disorder. Some of the risks hemophilia are: Scarring of the joints or joint disease, vision loss from bleeding of the eyes, chronic anemia from blood loss, a neurological or psychiatric problem, death which may occur from large amounts of blood loss or bleeding in the brain or other vital organs. Most cases of hemophilia are caused from inherited disorders but sometimes people can get it from vitamin K deficiency, liver disease, or treatments like prolonged use of antibiotics or anti coagulation drugs. Hemophilia is the best known bleeding disorder and it has had the most research done on it, so hemophiliacs have a slight advantage over people with other bleeding disorders.

To treat Hemophilia, a Clotting Factor is needed. It is in the shape of powder kept in a small, sterile glass bottle. It has to be kept in the fridge. When needed, The Clotting Factor is mixed with sterile water, then one minute later it can be injected into a vein. It may also be mixed with a large amount of water and injected through an IV.

There are over 140 centers that specialize in hemophilia. Most of these centers are "Comprehensive Care Facilities". Comprehensive care facilities provide all the services needed by a hemophiliac and their family. Services provided include: Primary physician, nurse coordinator, physiotherapist, and dentist. Hemophiliacs require a special dentist because of the higher risk of bleeding. It is recommended that hemophiliacs go to the treatment centers twice a year for a complete check-up.

The basic and most common treatment for patients with hemophilia A and B is factor replacement therapy. Factor replacement therapy is the IV injection of Factor VIII and IX concentrates which help control bleeding. This concentrate comes from two sources: human plasma and genetically engineered cells made by DNA technology. This concentrate is what the hemophiliac is lacking in their own genes. After the injection is given the patients blood becomes "normal" for a couple of hours which gives time for a clot to from at the site of a damaged blood vessel. This treatment is not a permanent cure, within about 3 days there is no trace left in the system. Today's Factor treatments are much more concentrated than they were in the past so very little is required even if the patient is going in for major surgery or has a major injury. Treatments are also very convenient, they can be stored at home in the fridge for up to 6 months. So if the patient is injured they don't need to go to the hospital they can give themself an injection at home. After the injection it only takes about 15-20 minutes for the clotting process to begin. There is a risk of contracting other disease such as AIDS from Factor VIII that is made from human plasma, but as technology gets better the cases of AIDS has dropped. There is no possibility of contracting diseases from genetic engineering Factor VIII.

Hemophiliacs can live a long life. The most common reason for early death among patients has been from AIDS related complications.

Any disorder caused totally or in part by a fault (or faults) of the genetic material passed from parent to child is considered a genetic disorder. The genes for many of these disorders are passed from one generation to the next, and children born with a heritable genetic disorder often have one or more extended family members with the same disorder. There are also genetic disorders that appear due to spontaneous faults in the genetic material, in which case a child is born with a disorder with no apparent family history.

Down Syndrome, also known as Trisomy 21, is a chromosome abnormality that effects one out of every 800-1000 newborn babies. During anaphase II of meiosis the sister chromatids of chromosome 21 fail to separate, resulting in an egg with an extra chromosome, and a fetus with three copies (trisomy) of this chromosome. At birth this defect is recognizable because of the physical features such as almond shaped eyes, a flattened face, and less muscle tone than a normal newborn baby. During pregnancy, it is possible to detect the Down Syndrome defect by doing amniocentesis testing. There is a risk to the unborn baby and it is not recommended unless the pregnant mother is over the age of thirty-five. Other non-lethal chromosomal abnormalities include additional osex chromosome abnormalities which is when a baby girl (about 1 in 2,500)is born with one x instead of two (xx) this can cause physical abnormalities and defective reproduction systems. Boys can also be born with extra X's (XXY or XXXY) which will cause reproductive problems and sometimes mental retardation.

Chromosomal Abnormalities In most cases with a chromosomal abnormality all the cells are affected. Defects can have anywhere from little effect to a lethal effect depending on the type of abnormality. Of the 1 in 200 babies born having some sort of chromosomal abnormality, about 1/3 of these results in spontaneous abortion. Abnormalities usually form shortly after fertilization and mom or dad usually has the same abnormality. There is no cure for these abnormalities. Tests are possible early in pregnancy and if a problem is detected the parents can choose to abort the fetus.

Mutation is a permanent change in a segment of DNA.

Mutations are changes in the genetic material of the cell. Substances that can cause genetic mutations are called mutagen agents. Mutagen agents can be anything from radiation from x-rays, the sun, toxins in the earth, air, and water viruses. Many gene mutations are completely harmless since they do not change the amino acid sequence of the protein the gene codes for.

Mutations can be good, bad, or indifferent. They can be good for you because their mutation can be better and stronger than the original. They can be bad because it might take away the survival of the organism. However, most of the time, they are indifferent because the mutation is no different than the original.

The not so harmless ones can lead to cancer, birth defects, and inherited diseases. Mutations usually happen at the time of cell division. When the cell divides, one cell contracts a defect, which is then passed down to each cell as they continue to divide.

Excerpt from:

Human Physiology/Genetics and inheritance - Wikibooks ...

Some people have earlobes that curve up between the lowest point of the earlobe and the point where the ear joins the head; these are known as "free" or "unattached" earlobes, as shown in the upper left of the picture below. Other people have earlobes that blend in with the side of the head, known as "attached" or "adherent" earlobes, as shown in the lower right.

Attached vs. free earlobes are often used to illustrate basic genetics. The myth is that earlobes can be divided into into two clear categories, free and attached, and that a single gene controls the trait, with the allele for free earlobes being dominant. Neither part of the myth is true.

Classroom exercises on earlobe genetics say that there are two distinct categories, free (F) and attached (A). However, many of the papers on earlobe genetics have pointed out that there are many people with intermediate earlobes (Quelprud 1934, Wiener 1937, Dutta and Ganguly 1965). El Kollali (2009) classified earlobes into three types, based on whether the attachment angle was acute, right, or obtuse. To make the picture above, I searched for pictures of professional bicyclists (because they have short hair), found 12 with their ears showing, and arranged them from free to attached. It doesn't look to me as if there are just two categories; instead, there is continuous variation in the height of the attachment point (the "otobasion inferius") relative to the lowest point on the earlobe (the "subaurale"). My own earlobes are exactly halfway in between the two extremes; I couldn't tell you whether my earlobes should be considered free or attached.

Carrire (1922) and Hilden (1922) were among the first to study the genetics of earlobes, and they reached opposite conclusions. Carrire (1922) looked at 15 families and concluded that attached earlobes were dominant. However, all of the offspring of A x A matings had attached earlobes, and there were no F x F matings, so his data are consistent with either free or attached being dominant.

Powell and Whitney (1937) looked at one family and concluded that attached earlobes were recessive. Wiener (1937) responded by pointing out that the "arbitrary classification into two sharply defined types...gives a false picture, since all gradations between the two extremes are encountered." He divided earlobes into four arbitrary groups, from 0 (completely free) to 3 (completely attached). All possible matings, from completely 0 x 0 to 3 x 3, produced some intermediate earlobes. Wiener (1937) concluded that earlobes were determined by more than one gene, or by a singe gene with more than two alleles.

Lai and Walsh (1966) called earlobes in which the lowest point on the earlobe was the attachment point "attached," and they classified all other earlobes as "free." They recorded the following data on families in New Guinea:

If the myth were true, two parents with attached earlobes could not have a child with a free earlobe. There are slightly more A offspring from A x A matings, but the large numbers of F offspring from A x A matings and A offspring from F x F matings indicate that this is not a one-locus, two-allele trait.

Mohanraju and Mukherjee (1973) performed a similar study in India and found similar results:

They found a much stronger association between parents and offspring, but the five F offspring of A x A matings are inconsistent with the myth that this is a one-locus, two-allele trait.

Earlobes do not fall into two categories, "free" and "attached"; there is continuous variation in attachment point, from up near the ear cartilage to well below the ear. While there is probably some genetic influence on earlobe attachment point, family studies show that it does not fit the simple one-locus, two-allele myth. You should not use earlobe attachment to demonstrate basic genetics.

Carrire, R. 1922. ber erbliche Orhformen, insbesondere das angewachsene Ohrlppchen. Zeitschrift fr Induktive Abstammungs- und Vererbungslehre 28: 288-242.

Dutta, P., and P. Ganguly. 1965. Further observations on ear lobe attachment. Acta Genetica 15: 77-86.

El Kollali, R. 2009. Earlobe morphology: a simple classification of normal earlobes. Journal of Plastic, Reconstructive and Aesthetic Surgery 62: 277-280.

Hilden, K. 1922. ber die Form des Ohrlppchens beim Menschen und ihre Abhngigkeit von Erblanglagen. Hereditas 3: 351-357.

Lai, L.Y.C., and R.J. Walsh. 1966. Observations on ear lobe types. Acta Genetica 16: 250-257.

Mohanraju, C., and D.P. Mukherjee. 1973. Ear lobe attachment in an Andhra village and other parts of India. Human Heredity 23: 288-297.

Mowlavi, A., D.G. Meldrum, and B.J. Wilhelmi. 2004. Earlobe morphology delineated by two components: the attached cephalic segment and the free caudal segment. Plastic and Reconstructive Surgery 113: 1075-1076.[not seen yet]

Powell, E.F., and D.D. Whitney. 1937. Ear lobe inheritance: an unusual three-generation photographic pedigree chart. Journal of Heredity 28: 184-186.

Quelprud, T. 1934. Familienforschungen ber Merkmale des usseren Ohres. Zeitschrift f Induktive Abstammungs- und Vererbungslehre 67: 296-299.

Wiener, A.S. 1937. Complications in ear genetics. Journal of Heredity 28: 425-426.

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Myths of Human Genetics: Earlobes