Monthly Archives: February 2017

February 23, 2017 This visual abstract depicts the findings of McCoy et al., who show genome-wide interrogation of the functional differences between modern human and Neanderthal alleles reveals that Neanderthal-inherited sequences are not silent remnants of ancient interbreeding but have a measurable impact on gene expression that may contribute to phenotypic variation in modern humans. Credit: McCoy et al./Cell 2017

The last Neanderthal died 40,000 years ago, but much of their genome lives on, in bits and pieces, through modern humans. The impact of Neanderthals' genetic contribution has been uncertain: Do these snippets affect our genome's function, or are they just silent passengers along for the ride? In Cell on February 23, researchers report evidence that Neanderthal DNA sequences still influence how genes are turned on or off in modern humans. Neanderthal genes' effects on gene expression likely contribute to traits such as height and susceptibility to schizophrenia or lupus, the researchers found.

"Even 50,000 years after the last human-Neanderthal mating, we can still see measurable impacts on gene expression," says geneticist and study co-author Joshua Akey of the University of Washington School of Medicine. "And those variations in gene expression contribute to human phenotypic variation and disease susceptibility."

Previous studies have found correlations between Neanderthal genes and traits such as fat metabolism, depression, and lupus risk. However, figuring out the mechanism behind the correlations has proved difficult. DNA can be extracted from fossils and sequenced, but RNA cannot. Without this source of information, scientists can't be sure exactly if Neanderthal genes functioned differently than their modern human counterparts. They can, however, look to gene expression in modern humans who possess Neanderthal ancestry.

In this study, researchers analyzed RNA sequences in a dataset called the Genotype-Tissue Expression (GTEx) Project, looking for people who carried both Neanderthal and modern human versions of any given geneone version from each parent. For each such gene, the investigators then compared expression of the two alleles head-to-head in 52 different tissues.

"We find that for about 25% of all those sites that we tested, we can detect a difference in expression between the Neanderthal allele and the modern human allele," says the study's first author, UW postdoctoral researcher Rajiv McCoy.

Expression of Neanderthal alleles tended to be especially low in the brain and the testes, suggesting that those tissues may have experienced more rapid evolution since we diverged from Neanderthals approximately 700,000 years ago. "We can infer that maybe the greatest differences in gene regulation exist in the brain and testes between modern humans and Neanderthals," says Akey.

One example uncovered by this study is a Neanderthal allele of a gene called ADAMTSL3 that decreases risk of schizophrenia, while also influencing height. "Previous work by others had already suggested that this allele affects alternative splicing. Our results support this molecular model, while also revealing that the causal mutation was inherited from Neanderthals," says McCoy. Alternative splicing refers to a process in which mRNAs are modified before they leave the cell's nucleus. When the Neanderthal mutation is present, the cell's machinery removes a segment of the mRNA that is expressed in the modern human version. The cell ends up making a modified protein because of a single mutation from a Neanderthal ancestor.

The connection between that modified protein, height, and schizophrenia still requires more investigation, but it's an example of how small differences between modern humans and Neanderthals can contribute to variation in people.

"Hybridization between modern humans and Neanderthals increased genomic complexity," explains Akey. "Hybridization wasn't just something that happened 50,000 years ago that we don't have to worry about anymore. Those little bits and pieces, our Neanderthal relics, are influencing gene expression in pervasive and important ways."

Next steps may include investigating whether Denisovansanother species of hominins that crossbred with modern humansare contributing to gene expression, as well as applying the side-by-side method of expression analysis more broadly. For this study, McCoy and his colleagues had to develop a new statistical approach to sift through the immense amount of RNA data, but the same technique could be used to compare gene expression differences between modern human alleles.

Explore further: Long ago humans and Neanderthals Interbred: What happened to Neanderthal genes?

More information: Cell, McCoy et al.: "Impacts of Neanderthal-introgressed sequences on the landscape of human gene expression" http://www.cell.com/cell/fulltext/S0092-8674(17)30128-9 , DOI: 10.1016/j.cell.2017.01.038

Journal reference: Cell

Provided by: Cell Press

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Neanderthal DNA contributes to human gene expression - Phys.Org

Crowd control: Nearly 4 percent of people carry at least one genetic variant tied to a serious medical condition.

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Most adults with genetic variants tied to certain conditions, such as heart disease or cancer, go undiagnosed, according to a study of more than 50,000 people1.

The variants silence leaves these people unaware of their risk of developing the conditions later in life, says lead investigator David Carey, director of the Weis Center for Research at Geisinger Health System in Danville, Pennsylvania.

Careys team looked for genetic variants associated with 27 chronic conditions. The list of conditions does not include autism, but does include tuberous sclerosis complex. As many as half of all people with tuberous sclerosis complex have autism. Other teams are studying the same population to gauge the effects of variants linked to autism.

The value lies in the huge population, all captured within the same healthcare system. Its really fantastic, says Dan Arking, associate professor of genetic medicine at Johns Hopkins University in Baltimore, Maryland, who was not involved in the new work.

The variants in the study are clinically significant: Some increase the risk of the linked condition by up to 70 percent. But variants interact with many other genetic and environmental factors, and these interactions may cause the conditions features to be more or less severe or even absent.

People used to say anytime there is a [spontaneous] variant or something really rare, that it must cause disease, says Arking. The new study instead suggests that, on the contrary, some rare variants have weak ties to conditions such as autism, he says. The results appeared 23 December in Science2.

Carey and his team looked at data from the MyCode Community Health Initiative, launched in 2007 by Geisinger Health System in central Pennsylvania. MyCode researchers have collected DNA samples and up to 14 years worth of medical records from the participants.

The researchers probed the 50,726 participants genomes for inserted or deleted sequences, and for single nucleotide variants, called SNVs, in the code. Their analysis revealed that each individual harbors about 21,409 SNVs, consistent with findings from previous studies.

The researchers then narrowed their analysis to 76 genes known to contribute to life-threatening conditions such as cancer or cardiovascular disease. The list includes three genes tied to tumor growth and to autism: PTEN, TSC1 and TSC2. (Clinicians are obligated to counsel individuals with variants in any of these 76 genes.)

Nearly 4 percent of the general population carries variants in at least one of these genes, the researchers found. But more than one-third of these people show no symptoms and have no family history of the linked condition. For example, most of the individuals who carry a variant linked to an inherited condition that causes high cholesterol have normal cholesterol levels, according to a second study by Careys team in the same issue of Science.

The findings could mean the individual will develop the condition later in life or not, Carey says. Other variants in her genome might mitigate the risk, he says.

We generally look at one gene at a time, but we have about 20,000 genes and they all work in concert, Carey says. Were not sophisticated enough yet to be able to tease out all the genetic interactions, but we know that they exist.

Last year, another team of researchers used the MyCode data to show that genetic changes tied to autism also crop up in many people without the condition. At the 2016 American Society of Human Genetics annual meeting in Vancouver, Canada, last year, they presented results showing that about 2,000 of the MyCode participants carry large deletions or duplications of genetic material associated with autism, intellectual disability or schizophrenia. But less than 5 percent of this group has received treatment for any of the conditions.

The finding suggests that genetic variants can confer features so subtle that they go unrecognized well into adulthood. Researchers could study this group to understand the mildest end of the autism spectrum.

This cohort could help us describe the full picture of autism, the breadth of the phenotype, says Christa Lese Martin, director of the Autism and Developmental Medicine Institute at Geisinger Health System in Lewisburg, Pennsylvania. Martin was a lead investigator on the autism study but was not involved in the new work.

About 125,000 people have enrolled in MyCode so far. By early next year, researchers expect to have sequencing data for 90,000 of the individuals.

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Many people with harmful genetic variants show no ill effects - Spectrum

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Fibrocell Announces Dosing of First Patient in Phase I/II Clinical Trial of FCX-007 Gene Therapy for Treatment of ... - P&T Community

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OCD-like behavior linked to genetic mutation - Science Daily