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PNAS Papers on Ultrarare Hearing Loss Variants, Telomeres with Human Herpesvirus Integration, More

Researchers at the Pasteur Institute and elsewhere describe ultrarare variants that appear to contribute to familial and sporadic forms of age-related hearing loss, called presbycusis. With exome sequencing on more than 100 familial cases, 122 sporadic cases, and 120 controls, the team searched for variants contributing to severe presbycusis cases in nearly three dozen known deafness-related genes, identifying ultrarare, predicted pathogenic variants in more than one quarter of the familial cases and in almost 23 percent of the sporadic cases. After digging into the pathogenicity of such variants in a series of follow-up analyses and experiments, the authors conclude that such ultrarare variants likely have a role in some forms of presbycusis. "Our findings demonstrate that the genetics of presbycusis is shaped by not only well-studied polygenic risk factors of small effect size revealed by common variants, but also ultrarare variants likely resulting in monogenic forms," they write, "thereby paving the way for treatments with emerging inner ear gene therapy."

A team from Germany and the US takes a look at the telomere regions of human cells infected with human herpesvirus 6A (HHV-6A) or human herpesvirus 6B (HHV-6B) with whole-genome optical mapping on patient cell lines containing HHV-6, which may integrate into the telomere region of infected cells. Along with fluorescent in situ hybridization methods to confirm findings from their optical mapping experiments, the researchers brought in genome sequence data to get a look at the integrated virus sites in the broader genome context. "Our results conclusively determine the orientation of the virus genome, as well as the length of the telomeric virus-chromosome junction and the distal telomeres on the end of the virus genome," they note, adding that "the ability to determine the chromosomal location of the virus will be crucial to decipher the role of the integrated virus genome in human diseases."

Investigators in the UK and the US present findings from a study on factors influencing variable transposable element methylation patterns in the genetically identical mice. Based on findings from genome-wide screening experiments done in mouse models with "variably methylated intracisternal A-particle" epialleles, the team focused in on a group of KRAB zinc finger protein (KZFP)-coding genes that appeared to influence methylation profiles in those variable regions. From these and other results, the study's authors suggest that "rapid KZFP divergence underlies variable epigenetic states in mammals, with implications for epigenetically conferred phenotypic differences between individuals within and across generations."