Category Archives: Human Genetics

PUBLIC RELEASE DATE:

25-Dec-2013

Contact: Emily Ng eng3@nshs.edu 516-562-2670 North Shore-Long Island Jewish (LIJ) Health System

MANHASSET, NY An international group of investigators has discovered new genes, pathways and cell types that are involved in inherited susceptibility to rheumatoid arthritis (RA). The findings are published online in Nature.

Scientists performed a genome-wide association study (GWAS) meta-analysis in more than 100,000 people of European and Asian descent. They discovered 42 new sites of genetic variation involved in risk for RA. The analysis provides specific locations of genes, DNA sequences or positions on chromosomes for these genetic differences, bringing the catalog of confirmed risk variants for RA to over 100 genetic loci. These findings lead to a better understanding of how new treatments could be developed.

"This study is the culmination of over a decade of work by an extraordinary group of collaborative scientists from around the world," said Peter K. Gregersen, a collaborator on the study, and head of the Robert S. Boas Center for Genomics and Human Genetics at the Feinstein Institute for Medical Research. "It provides us with a definitive list of the major common genetic variation involved in this disease, and points the way forward to develop new diagnostic and therapeutic approaches to this illness."

The lead investigator of the study, Robert Plenge, MD, PhD, director of Genetics and Genomics, Division of Rheumatology, Immunology and Allergy at Brigham and Women's Hospital added, "Our study provides a compelling link between human genetics in RA and approved therapies to treat RA. This leads to an intriguing question: can our new genetic discoveries lead to new therapies to treat or cure RA? Further, can a similar approach be used to develop therapies for other complex diseases such as lupus, diabetes and Alzheimer's disease?"

Rheumatoid arthritis is a long-term inflammatory disorder that may affect many tissues and organs, but principally attacks flexible joints. It can be a disabling and painful condition, which can lead to substantial loss of functioning and mobility if not adequately treated. The disease often leads to the destruction of cartilage and fusion of the joints. Rheumatoid arthritis can also produce inflammation in areas of the body including the lungs, membrane around the heart, and white of the eye.

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Feinstein Institute researchers are conducting studies on rheumatoid arthritis, both on genetics as well as to identify targets for the development of new therapies. To learn more, visit http://www.FeinsteinInstitute.org.

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Researchers complete a milestone in defining the genetic basis of rheumatoid arthritis

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Newswise BIRMINGHAM, Ala. Changes to a gene called LZTR1 predispose people to develop a rare disorder where multiple tumors called schwannomas form near nerve pathways, according to a study published today in the journal Nature Genetics and led by researchers from the University of Alabama at Birmingham.

The formation of multiple schwannomas is one sign that a person has the genetic disorder called schwannomatosis, which is one of the three major forms of neurofibromatosis, besides neurofibromatosis types 1 and 2. The condition is so named because the tumors originate in Schwann cells that form in sheaths that insulate nerves to cause severe, chronic pain in many patients.

To date, physicians cannot give most patients a confirmed diagnosis for schwannomatosis, even if they show symptoms, because changes in genes linked to the condition by past studies explain only about 50 percent of familial and less than 10 percent of sporadic cases.

Work in 2007 determined that inheritable mutations in SMARCB1 predisposed to schwannomatosis. In addition, the schwannomas showed a loss of the long arm of chromosome 22, and different mutations in the neurofibromatosis type 2 (NF2) gene were found in each tumor studied.

Despite these many known details, much of the risk for schwannomatosis remained unexplained going into the current study. Several research groups had proposed that other schwannomatosis-predisposing genes existed, but no one had found any. Specializing in genetic studies for all forms of the neurofibromatoses, the UAB Medical Genomics Laboratory chose to focus its research on a subset of schwannomatosis samples that did not harbor SMARCB1 mutations, which framed their experiments such that the role of LZTR1 was revealed.

We have been working urgently to identify the genetic mechanisms behind these diseases because doing so is central to efforts to understand schwannoma tumor development as well as to identify new drug treatments, said Ludwine Messiaen, Ph.D., director of the Medical Genomics Laboratory, professor in the Division of Clinical Genetics in the Department of Genetics within the UAB School of Medicine and corresponding study author. This is pertinent as only some of the schwannomas can be surgically removed without neurological consequences, and there is no widely accepted approach for treating the severe, chronic pain in these patients.

The study, conceived and coordinated by Arkadiusz Piotrowski of the University of Gdansk in Poland and Messiaen, resulted in the identification of LZTR1 on chromosome 22q as a novel tumor-suppressor gene predisposing to multiple schwannomas in patients without a mutation in SMARCB1. The results were seen in patients whose schwannomas also showed a loss of the long arm of chromosome 22 and a different somatic NF2 mutation in each tumor. The team found that in all 25 schwannomas studied from 16 unrelated schwannomatosis patients, all tumors showing a loss of the long arm of chromosome 22 and a different somatic NF2 mutation in each tumor also had LZTR1 mutations present, strongly supporting the contribution to the disease by the combination of these factors.

The LZTR1 mutations were found using massive parallel sequencing (e.g. next-generation sequencing) of highly evolutionary conserved sequences specifically on chromosome 22. LZTR1 mutations likely will be found in a high fraction of familial as well as sporadic schwannomatosis patients, whose predisposition is not caused by SMARCB1, says Messiaen. Indeed, LZTR1 mutations were found in 6/6 familial and 8/11 sporadic such patients. Both causal genes, LZTR1 and SMARCB1, show a potential functional link to chromatin remodeling mechanisms, which play a crucial role in cell differentiation and adaptation to environmental stimuli. Further, LZTR1 and SMARCB1 are known to interact with histone deacetylase 4 or HDAC4, which is a target for histone deacetylase inhibitors, a new class of anti-tumor drugs. The present findings will encourage further studies aiming at potential treatment for schwannomatosis.

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Changes in Gene Explain More of Inherited Risk for Rare Disease

GAINESVILLE, Fla., Dec. 23 (UPI) -- Human-induced climate change may pose a bigger threat than first believed to plants and global agriculture, a University of Florida scientist says.

Evolutionary genetics Professor Pam Soltis, co-author of a study published in the journal Nature, said most flowering plants, trees and agricultural crops may not have the evolutionary traits needed to rapidly respond to human-induced climate change.

Many of these plants needed millions of years to evolve mechanisms to cope with freezing temperatures as they radiated into nearly every climate during pre-historic times, she said, and likely acquired many of these adaptive traits prior to their movement into colder regions.

"Only some plants were able to make the adjustments to survive in cold climates," Soltis said in a university release Friday. "In fact, some had traits used for other purposes that they co-opted for cold tolerance. The results have implications for plant response to climate change -- some plant lineages, including many crops, will not have the underlying genetic attributes that will allow for rapid responses to climate change."

Because evolutionary strategies to resist cold would have taken millions of years, researchers said, it could mean many plants will have trouble with accelerating human-caused climate change.

"Some of these changes were probably not as simple as we once thought," Soltis said. "Adjusting to big shifts in their environments is probably not easy for plants to do.

"With climate change that is human-induced, all habitats will be affected over a short period of time, and plants and other organisms will have to adapt quickly if they are to survive," she said.

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Study: Some plants won't cope with human-induced climate change

Human genetic variation is the genetic differences both within and among populations. There may be multiple variants of any given gene in the human population (genes), leading to polymorphism. Many genes are not polymorphic, meaning that only a single allele is present in the population: the gene is then said to be fixed.[1] On average, biochemically all humans are 99.9% similar to any other humans.[2]

No two humans are genetically identical. Even monozygotic twins, who develop from one zygote, have infrequent genetic differences due to mutations occurring during development and gene copy number variation.[3] Differences between individuals, even closely related individuals, are the key to techniques such as genetic fingerprinting. Alleles occur at different frequencies in different human populations, with populations that are more geographically and ancestrally remote tending to differ more.

Causes of differences between individuals include the exchange of genes during meiosis and various mutational events. There are at least two reasons why genetic variation exists between populations. Natural selection may confer an adaptive advantage to individuals in a specific environment if an allele provides a competitive advantage. Alleles under selection are likely to occur only in those geographic regions where they confer an advantage. The second main cause of genetic variation is due to the high degree of neutrality of most mutations. Most mutations do not appear to have any selective effect one way or the other on the organism. The main cause is genetic drift, this is the effect of random changes in the gene pool. In humans, founder effect and past small population size (increasing the likelihood of genetic drift) may have had an important influence in neutral differences between populations. The theory that humans recently migrated out of Africa supports this.

The study of human genetic variation has both evolutionary significance and medical applications. It can help scientists understand ancient human population migrations as well as how different human groups are biologically related to one another. For medicine, study of human genetic variation may be important because some disease-causing alleles occur more often in people from specific geographic regions. New findings show that each human has on average 60 new mutations compared to their parents.[4][5] Apart from mutations, many genes that may have aided humans in ancient times plague humans today. For example, it is suspected that genes that allow humans to more efficiently process food are those that make people susceptible to obesity and diabetes today.[6]

Genetic variation among humans occurs on many scales, from gross alterations in the human karyotype to single nucleotide changes.[7]

Nucleotide diversity is the average proportion of nucleotides that differ between two individuals. The human nucleotide diversity is estimated to be 0.1%[8] to 0.4% of base pairs.[9] A difference of 1 in 1,000 amounts to approximately 3 million nucleotide differences, because the human genome has about 3 billion nucleotides.

A single nucleotide polymorphism (SNP) is difference in a single nucleotide between members of one species that occurs in at least 1% of the population. It is estimated that there are 10 to 30 million SNPs in humans.

SNPs are the most common type of sequence variation, estimated to comprise 90% of all sequence variations.[10] Other sequence variations are single base exchanges, deletions and insertions.[10] SNPs occur on average about every 100 to 300 bases [10] and so are the major source of heterogeneity.

A functional, or non-synonymous, SNP is one that affects some factor such as gene splicing or messenger RNA, and so causes a phenotypic difference between members of the species. About 3% to 5% of human SNPs are functional (see International HapMap Project). Neutral, or synonymous SNPs are still useful as genetic markers in genome-wide association studies, because of their sheer number and the stable inheritance over generations.[10]

A coding SNP is one that occurs inside a gene. There are 105 Human Reference SNPs that result in premature stop codons in 103 genes. This corresponds to 0.5% of coding SNPs. They occur due to segmental duplication in the genome. These SNPs result in loss of protein, yet all these SNP alleles are common and are not purified in negative selection.[11]

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Human genetic variation - Wikipedia, the free encyclopedia

Volume93,Issue 6:December5,2013

On the cover: John Borden Graham, M.D., President, American Society of Human Genetics, 1972. John Graham is remembered as a pioneer in the genetics of blood coagulation and genetics education. He was born in 1918 in Goldsboro and earned a bachelors degree from Davidson College in 1938. He began his medical training by studying the basic sciences at University of North Carolina at Chapel Hill (UNC-CH) and completed his M.D. at Cornell University in 1942. After a short pathology residency, he entered the US Army, where he served as a surgeon in the Pacific Theater. He returned to Chapel Hill in 1946 to join the Department of Pathology as an instructor. He remained at UNC-CH until his formal retirement in 1985. Graham continued to participate in departmental activities and attended departmental grand rounds until the day before his death in 2004. In 1954, Graham established the first formal course in medical genetics at UNC-CH. Grahams research focused on hematology and blood clotting initially through collaboration with Kenneth Brinkhous, who was characterizing canine hemophilia. Together, they demonstrated X-linkage and viability of homozygous females (Brinkhous and Graham [1950]. Science 111, 723724). He is credited with the characterization of clotting factor X and X-linked vitamin-D-resistant rickets. He remembered when the Society numbered 200 members in 1954 and that meetings were held during summer vacations on university campuses with families in tow. He contrasted those days with the very large Society meetings held at posh urban hotels in the mid-1980s (Graham [1985], Norma Berryhill Distinguished Lecture, https://secure.dev.unc.edu/MedFound/graham13-27.pdf). Although no recording of his presidential address from the 1972 annual meeting held in Philadelphia can be found, some of Grahams articles represent recorded presentations. Examples include his 1956 review of hemophilia drawn from a session at the 1955 ASHG annual meeting (Am. J. Hum. Genet. 8, 6379) and a 1959 discussion on vascular hemophilia, which includes references to Homers Odyssey (J. Med. Educ. 34, 385396). These allow the reader to enjoy Grahams garrulous and erudite style. This image of Graham was drawn by Peter James Field from a photograph provided by the University of North Carolina Department of Pathology and is used with permission.

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Each week, The American Journal of Human Genetics publishes papers online ahead of the print issue. Here are the latest:

All in the Family In the age of next-generation sequencing, linkage analysis might seem old fashioned, and perhaps even ill suited for the pursuit of variants that contribute to complex phenotypes. Indeed, many have turned to genome-wide association studies and exome-wide sequencing studies for such investigations. In this issue, Rosenthal et al. show that family studies can be adapted, and indeed strengthened, by the integration with 21st century technology and resources. Through a combination of linkage analysis and exome sequencing, the authors identified a SLC25A40 missense change that might contribute to high triglyceride levels. They then harnessed the power of the NHLBI Exome Sequencing Project to identify an association between SLC25A40 variants and high triglyceride levels.

Regulating lincRNA Expression Unlike that of protein-coding genes, the function of the majority of large intergenic noncoding RNAs (lincRNAs) remains unknown. To gain further insight into the potential roles of lincRNAs, Popadin et al. used a genome-wide approach to characterize the cis expression quantitative trait loci (cis-eQTLs) and DNA-methylation patterns that contribute to lincRNA expression variability across fibroblasts, lymphoblastoid cell lines, and T cells derived from 195 European individuals. In general, lincRNA cis-eQTLs affected neighboring downstream protein-coding genes, suggesting that lincRNAs might also act as enhancers. Because lincRNAs are relatively young, it remains to be seen whether the variants that contribute to variable expression are under selection.

Functional Characterization of Breast-Cancer-Associated SNPs Variants near FGFR2 have been implicated in estrogen receptor (ER)-positive breast cancer, but it remains unclear how this locus contributes to disease progression. In this study, Meyer et al. used the iCOGS chip to fine map this region. They identified three independent risk signals and further prioritized the variants by using a variety of assays. ChIP assays demonstrated allele-specific binding of FOXA1 and E2F1. Because FOXA1 and ER are involved in conferring estrogen responsiveness, these results support the involvement of this locus in ER-positive breast cancer.

Ciliary Involvement in Morbid Obesity Substantial effort has been spent on identifying genes that are associated with obesity and metabolic dysfunction. In this issue, Shalata and colleagues identified a homozygous nonsense mutation in CEP19 in a large, consanguineous family where affected individuals are morbidly obese and have an average body mass index of 48.7. Moreover, Cep19-knockout mice were nearly twice as heavy as their wild-type littermates, as well as hyperphagic, glucose intolerant, and insulin resistant in comparison to the wild-type mice. CEP19 localized to the centriole and basal body of primary cilia, suggesting the need for further explorations into the role of cilia in regulating metabolism.

Exploring T2D Exomes In recent years, the hunt for variants associated with common diseases has focused on uncovering common variants. More recently, however, spurred by the decreased cost of sequencing, investigators have begun to search for rare variants of large effect. In this issue, Lohmueller et al. explore the possibility that the underlying genetic architecture of type 2 diabetes (T2D) is driven by rare variants clustered in a small number of genes. Single-marker and gene-based association tests failed to reveal significant associations, suggesting that if rare variants do contribute to T2D risk, they will not be limited to a small number of genes.

A Polymorphism in IRF4 Affects Human Pigmentation through a Tyrosinase-Dependent MITF/TFAP2A Pathway In this study, Praetorius et al. demonstrate that a SNP associated with sun-exposure sensitivity lies within a melanocyte-specific enhancer of IRF4 transcription, thus identifying a noncoding polymorphism that affects a phenotype through modulation of a developmental gene regulatory network.

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The American Journal of Human Genetics - Cell

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Dr. Karin Blakemore
Dr. Blakemore is the Director of Maternal Fetal Medicine and Prenatal Genetics whose clinical practice focuses on caring for expectant mothers and their deve...

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Dr. Karin Blakemore - Video

Human genetics is the study of inheritance as it occurs in human beings. Human genetics encompasses a variety of overlapping fields including: classical genetics, cytogenetics, molecular genetics, biochemical genetics, genomics, population genetics, developmental genetics, clinical genetics, and genetic counseling.

Genes can be the common factor of the qualities of most human-inherited traits. Study of human genetics can be useful as it can answer questions about human nature, understand the diseases and development of effective disease treatment, and understand genetics of human life. This article describes only basic features of human genetics; for the genetics of disorders please see: Medical genetics.

Inheritance of traits for humans are based upon Gregor Mendel's model of inheritance. Mendel deduced that inheritance depends upon discrete units of inheritance, called factors or genes.[1]

Autosomal traits are associated with a single gene on an autosome (non-sex chromosome)they are called "dominant" because a single copyinherited from either parentis enough to cause this trait to appear. This often means that one of the parents must also have the same trait, unless it has arisen due to a new mutation. Examples of autosomal dominant traits and disorders are Huntington's disease, and achondroplasia.

Autosomal recessive traits is one pattern of inheritance for a trait, disease, or disorder to be passed on through families. For a recessive trait or disease to be displayed two copies of the trait or disorder needs to be presented. The trait or gene will be located on a non-sex chromosome. Because it takes two copies of a trait to display a trait, many people can unknowingly be carriers of a disease. From an evolutionary perspective, a recessive disease or trait can remain hidden for several generations before displaying the phenotype. Examples of autosomal recessive disorders are albinism, cystic fibrosis, Tay-Sachs disease.

X-linked genes are found on the sex X chromosome. X-linked genes just like autosomal genes have both dominant and recessive types. Recessive X-linked disorders are rarely seen in females and usually only affect males. This is because males inherit their X chromosome and all X-linked genes will be inherited from the maternal side. Fathers only pass on their Y chromosome to their sons, so no X-linked traits will be inherited from father to son. Men cannot be carriers for recessive X linked traits, as they only have one X chromosome, so any X linked trait inherited from the mother will show up.

Females express X-linked disorders when they are homozygous for the disorder and become carriers when they are heterozygous. X-linked dominant inheritance will show the same phenotype as a heterozygote and homozygote. Just like X-linked inheritance, there will be a lack of male-to-male inheritance, which makes it distinguishable from autosomal traits. One example of a X-linked trait is Coffin-Lowry syndrome, which is caused by a mutation in ribosomal protein gene. This mutation results in skeletal, craniofacial abnormalities, mental retardation, and short stature.

X chromosomes in females undergo a process known as X inactivation. X inactivation is when one of the two X chromosomes in females is almost completely inactivated. It is important that this process occurs otherwise a woman would produce twice the amount of normal X chromosome proteins. The mechanism for X inactivation will occur during the embryonic stage. For people with disorders like trisomy X, where the genotype has three X chromosomes, X-inactivation will inactivate all X chromosomes until there is only one X chromosome active. Males with Klinefelter syndrome, who have an extra X chromosome, will also undergo X inactivation to have only one completely active X chromosome.

Y-linked inheritance occurs when a gene, trait, or disorder is transferred through the Y chromosome. Since Y chromosomes can only be found in males, Y linked traits are only passed on from father to son. The testis determining factor, which is located on the Y chromosome, determines the maleness of individuals. Besides the maleness inherited in the Y-chromosome there are no other found Y-linked characteristics.

A pedigree is a diagram showing the ancestral relationships and transmission of genetic traits over several generations in a family. Square symbols are almost always used to represent males, whilst circles are used for females. Pedigrees are used to help detect many different genetic diseases. A pedigree can also be used to help determine the chances for a parent to produce an offspring with a specific trait.

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Human genetics - Wikipedia, the free encyclopedia

Human evolutionary genetics studies how one human genome differs from the other, the evolutionary past that gave rise to it, and its current effects. Differences between genomes have anthropological, medical and forensic implications and applications. Genetic data can provide important insight into human evolution.

Biologists classify humans, along with only a few other species, as great apes (species in the family Hominidae). The Hominidae include two distinct species of chimpanzee (the bonobo, Pan paniscus, and the common chimpanzee, Pan troglodytes), two species of gorilla (the western gorilla, Gorilla gorilla, and the eastern gorilla, Gorilla graueri), and two species of orangutan (the Bornean orangutan, Pongo pygmaeus, and the Sumatran orangutan, Pongo abelii).

Apes, in turn, belong to the primates order (>400 species). Data from both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) indicate that primates belong to the group of Euarchontoglires, together with Rodentia, Lagomorpha, Dermoptera, and Scandentia.[1] This is further supported by Alu-like short interspersed nuclear elements (SINEs) which have been found only in members of the Euarchontoglires.[2]

A phylogenetic tree like the one shown above is usually derived from DNA or protein sequences from populations. Often mitochondrial DNA or Y chromosome sequences are used to study ancient human demographics. These single-locus sources of DNA do not recombine and are almost always inherited from a single parent, with only one known exception in mtDNA.[3] Individuals from the various continental groups tend to be more similar to one another than to people from other continents. The tree is rooted in the common ancestor of chimpanzees and humans, which is believed to have originated in Africa. Horizontal distance in the diagram corresponds to two things:

Chimpanzees and humans belong to different genera, indicated in red. Formation of species and subspecies is also indicated, and the formation of races is indicated in the green rectangle to the right (note that only a very rough representation of human phylogeny is given). Note that vertical distances are not meaningful in this representation.

The separation of humans from their closest relatives, the African apes (chimpanzees and gorillas), has been studied extensively for more than a century. Five major questions have been addressed:

As discussed before, different parts of the genome show different sequence divergence between different hominoids. It has also been shown that the sequence divergence between DNA from humans and chimpanzees varies greatly. For example the sequence divergence varies between 0% to 2.66% between non-coding, non-repetitive genomic regions of humans and chimpanzees.[5] Additionally gene trees, generated by comparative analysis of DNA segments, do not always fit the species tree. Summing up:

The divergence time of humans from other apes is of great interest. One of the first molecular studies, published in 1967 measured immunological distances (IDs) between different primates.[7] Basically the study measured the strength of immunological response that an antigen from one species (human albumin) induces in the immune system of another species (human, chimpanzee, gorilla and Old World monkeys). Closely related species should have similar antigens and therefore weaker immunological response to each other's antigens. The immunological response of a species to its own antigens (e.g. human to human) was set to be 1.

The ID between humans and gorillas was determined to be 1.09, that between humans and chimpanzees was determined as 1.14. However the distance to six different Old World monkeys was on average 2.46, indicating that the African apes are more closely related to humans than to monkeys. The authors consider the divergence time between Old World monkeys and hominoids to be 30 million years ago (MYA), based on fossil data, and the immunological distance was considered to grow at a constant rate. They concluded that divergence time of humans and the African apes to be roughly ~5 MYA. That was a surprising result. Most scientists at that time thought that humans and great apes diverged much earlier (>15 MYA).

The gorilla was, in ID terms, closer to human than to chimpanzees; however, the difference was so slight that the trichotomy could not be resolved with certainty. Later studies based on molecular genetics were able to resolve the trichotomy: chimpanzees are phylogenetically closer to humans than to gorillas. However, the divergence times estimated later (using much more sophisticated methods in molecular genetics) do not substantially differ from the very first estimate in 1967.

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Human evolutionary genetics - Wikipedia, the free encyclopedia