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Nature Papers on Esophageal Cancer, Origin of Modern Horses, Exome Sequencing of UK Biobank Participants

A study examining the impact of genetics and the environment on the esophageal squamous cell carcinoma (ESCC) is published in Nature Genetics this week, revealing a mutation that appears crucial to the development of the disease. ESCC is one of the most frequent causes of cancer deaths worldwide and shows a remarkable variation in incidence globally that is not fully explained by known lifestyle and environmental risk factors. To investigate whether an unknown specific environmental mutagen is behind the large differences in ESCC incidence, a team led by scientists from the Wellcome Sanger Institute combined whole-genome sequencing and mutational signature analysis with extensive epidemiological questionnaire data for ESCC from eight countries with varying incidence rates. They find that the overall mutational profile of ESCC is extremely consistent, only deviating in rare cases that are most often due to DNA mismatch repair defects. Notably, they also find a near-universal presence of apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC)-associated mutational signatures in ESCC cases. "Although we did not find any evidence of a mutational signature capable of explaining the observed differences in incidence rates …  activation of APOBEC-driven mutagenesis appears to be a mandatory step in the oncogenesis of most ESCC," the study's authors write. "Further study of factors driving APOBEC activation, as well as in-depth studies of ESCC tumor evolution, are likely to yield additional insights."

A new study appearing in Nature this week suggests that the modern domestic horse may have originated in the Western Eurasian steppe more than 4,200 years ago. The work also uncovers genomic regions associated with traits favorable to horseback riding. Horse domestication transformed long-range travel and warfare, but the genetic, geographic, and temporal origins of modern domestic horses remain unknown. In an effort to identify the origin of the modern domestic horse, a group led by researchers from Université Paul Sabatier analyzed DNA from the remains of 273 ancient horses found in locations considered to be regions of horse domestication including Iberia, Anatolia, and the steppes of Western Eurasia and Central Asia. They identify the Western Eurasian steppes, especially the lower Volga-Don region, as the homeland of modern domestic horses. The scientists also find that equestrianism is strongly linked to critical locomotor and behavioral adaptations, such as endurance and weight-bearing ability, at two genes, GSDMC and ZFPM1. Based on these and other findings, the study's authors propose that, with the advent of horseback riding and spoke-wheeled chariots, modern domestic horses ultimately replaced almost all other horse populations as they expanded rapidly across Eurasia from about 2000 BC. GenomeWeb has more on this, here.

The exome sequencing of 454,787 UK Biobank study participants is reported by a Regeneron Genetics Center team in Nature this week, highlighting the ability of exome sequencing  to identify novel gene-trait associations, elucidate gene function, and pinpoint effector genes underlying genome-wide association study signals at scale. In the work, the researchers identify 12.3 million variants in 39 million base pairs across the coding regions of 18,893 genes, of which 99.6 percent were rare variants. Among the variants identified were 3,457,173 synonymous, 7,878,586 missense, and 915,289 putative loss-of-function variants, of which about half were observed only once in the dataset. About 23 percent of the missense variants were predicted to be deleterious using prediction algorithms. "This unique catalog of coding variation, combined with the large sample size and thousands of available phenotypes, provides a unique opportunity to assess gene function at unprecedented scale," the scientists write. GenomeWeb also has more on this, here.