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Genomics in the Journals: Apr 3, 2014

NEW YORK (GenomeWeb News) – A pair of Nature Genetics studies described mutations in a telomere-related gene called protection of telomerase 1 (POT1) that are associated with higher-than-usual risk of melanoma skin cancer.

The National Cancer Institute's Maria Teresa Landi and colleagues unearthed POT1 mutations as part of their whole-exome sequencing study of more than 100 individuals from Italian families affected by cutaneous malignant melanoma. The 56 families considered in the analysis did not appear to carry alterations in genes such as CDKN2A or CDK4 that have previously been implicated in melanoma.

Within the exomes, the team saw the same rare missense mutation in the POT1 gene in individuals from five families with higher-than-usual risk of cutaneous malignant melanoma.

The researchers didn't see that POT1 variant when they did genotyping on thousands of melanoma-free controls from the same population or when they searched several sequence databases, though they did detect it in an Italian individual with sporadic melanoma.

Through follow-up analyses, they found other rare changes in POT1 in Italian individuals with cutaneous malignant melanoma and in a subset of melanoma-prone families from the US and France that were tested for the study.

Meanwhile, an international team led by investigators in the UK and Australia used a combination of exome- and whole-genome sequencing to look for new melanoma risk genes.

Through exome sequencing on 168 melanoma-affected individuals from families in the UK, the Netherlands, and Australia, along with genome sequencing on 16 individuals with melanoma from those pedigrees, that group picked up on the presence of loss-of-function POT1 variants in individuals from four of the families.

Such changes appeared to be particularly common in individuals prone to early onset melanoma and multiple primary tumors, authors of that study noted. As in the other study, their results suggested that genetic glitches in POT1 can compromise proper telomere maintenance, leading to long telomeres and a related rise in melanoma risk.

Individuals from European populations are far more apt to carry lipid catabolism genes inherited from ancient Neanderthal ancestors than are other populations from outside of Africa, according to a Nature Communications study.

A team from China, Russia, and Germany used available Neanderthal, chimpanzee, and human genome sequences to explore the distribution and frequency of Neanderthal-related variants in the genomes of individuals from 11 present-day populations with ancestry from Africa, Asia, and Europe.

The researchers found Neanderthal-like SNPs at similar overall frequencies across the genomes of individuals from all of the non-African populations. But in individuals with European ancestry, those Neanderthal-related regions tended to cluster around genes involved in lipid breakdown.

Those lipid catabolism genes contained up to three times as many Neanderthal-descended SNPs in Europeans compared to other populations, the study's authors reported. They also showed signs of recent positive selection not detected in populations from Asia or Africa, apparently leading to differences in some lipid concentrations and related enzyme activity.

In particular, the group's efforts to assess transcriptional and metabolite differences associated with lipid catabolism variants inherited from Neanderthals hinted that the sequences are associated with different lipid concentrations in the brain, though more research is needed to explore the consequences of those lipid level changes.

"We don't know what these lipid concentration changes do to the brain," co-corresponding author Philipp Khaitovich, a researcher affiliated with the Max Planck Institute for Evolutionary Anthropology and China's CAS-MPG Partner Institute for Computational Biology, noted in a statement, "but the fact that Neanderthal variants might have changed our brain composition has interesting implications."

A Current Biology study provides evidence suggesting that individuals migrating from eastern Africa to southern Africa brought the pastoralist lifestyle to that part of the continent, leaving traces of their genetic ancestry in present-day members of the Khoe population.

Researchers from Sweden, France, and South Africa did targeted sequencing on 267 individuals from 13 populations in southern Africa, focusing on a regulatory region containing variants implicated in lactase persistence — the ability to continue digesting the milk sugar lactose in adulthood with the help of a lactase enzyme.

A closer look at the lactase persistence allele patterns in the populations indicated that a pastoralist herding population in southern Africa known as the Khoe shares a lactase persistence allele with pastoralist populations from eastern Africa. In contrast, the team did not detect such genetic signatures in the San, a southern African hunter-gatherer population that shares other genetic features with the Khoe.

Based on the selection patterns associated with the variant and its frequency in the populations considered, the study's authors concluded that the lactose-related allele likely arrived in southern Africa as the result of migration by a small group of pastoralists from eastern Africa. Once there, they appear to have interacted with the ancestors of existing Khoe populations, leaving their genetic and lifestyle marks in the region.

"The spread of pastoralism to southern Africa has been debated for many decades. We show that the spread was mediated by migration from eastern Africa," Uppsala University's Mattias Jakobsson, the study's senior author, said in a statement. "It is remarkable that a small group of migrants likely had a very strong impact on the way of life of the ancestors of the Khoe people."