Associations of autozygosity with a broad range of human phenotypes

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding

Ancient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis

© 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by homozygous or compound heterozygous gain-of-function mutations in MEFV, which encodes pyrin, an inflammasome protein. Heterozygous carrier frequencies for multiple MEFV mutations are high in several Mediterranean populations, suggesting that they confer selective advantage. Among 2,313 Turkish people, we found extended haplotype homozygosity flanking FMF-associated mutations, indicating evolutionarily recent positive selection of FMF-associated mutations. Two pathogenic pyrin variants independently arose >1,800 years ago. Mutant pyrin interacts less avidly with Yersinia pestis virulence factor YopM than with wild-type human pyrin, thereby attenuating YopM-induced interleukin (IL)-1β suppression. Relative to healthy controls, leukocytes from patients with FMF harboring homozygous or compound heterozygous mutations and from asymptomatic heterozygous carriers released heightened IL-1β specifically in response to Y. pestis. Y. pestis-infected MefvM680I/M680I FMF knock-in mice exhibited IL-1-dependent increased survival relative to wild-type knock-in mice. Thus, FMF mutations that were positively selected in Mediterranean populations confer heightened resistance to Y. pestis11sci

Surgical Management of Melanoma in Situ on Chronically Sun-Damaged Skin

Lentigo maligna (LM) commonly presents as a slow-growing pigmented macular lesion in chronically sun-damaged skin and may progress to invasive melanoma. Many regard it as a subtype of melanoma in situ (MIS), and surgical excision remains the preferred treatment, but standard 5-mm surgical margins recommended for typical MIS are often insufficient for LM due to its indistinct borders both clinically and histologically. A search of the literature was conducted to review specialized surgical techniques for the treatment of LM, focusing on methods that employ total peripheral margin assessment prior to definitive closure, using either frozen or permanent histologic sections. Many investigators have reported surgical modalities utilizing permanent sections for margin control, including variations of the "square" procedure and "perimeter" technique. Recurrence rates are low with these methods, but only short-term data have been reported. Similarly, several studies have demonstrated the efficacy of Mohs micrographic surgery (MMS) for treatment of MIS, with recurrence rates generally less than 1% over 3 to 5 years of follow-up. Many investigators have had success with immunohistochemical stains to identify melanocytes on frozen sections, aiding margin assessment in MMS. Compared to standard excision, methods that employ surgical margin control offer superior cure rates for LM and should be utilized when available. Total peripheral margin assessment using staged excisions and permanent sections is a simple and effective alternative to MMS for institutions that lack the resources for intraoperative frozen section analysis