Population Bottlenecks as a Potential Major Shaping Force of Human Genome Architecture

The modern synthetic view of human evolution proposes that the fixation of novel mutations is driven by the balance among selective advantage, selective disadvantage, and genetic drift. When considering the global architecture of the human genome, the same model can be applied to understanding the rapid acquisition and proliferation of exogenous DNA. To explore the evolutionary forces that might have morphed human genome architecture, we investigated the origin, composition, and functional potential of numts (nuclear mitochondrial pseudogenes), partial copies of the mitochondrial genome found abundantly in chromosomal DNA. Our data indicate that these elements are unlikely to be advantageous, since they possess no gross positional, transcriptional, or translational features that might indicate beneficial functionality subsequent to integration. Using sequence analysis and fossil dating, we also show a probable burst of integration of numts in the primate lineage that centers on the prosimian–anthropoid split, mimics closely the temporal distribution of Alu and processed pseudogene acquisition, and coincides with the major climatic change at the Paleocene–Eocene boundary. We therefore propose a model according to which the gross architecture and repeat distribution of the human genome can be largely accounted for by a population bottleneck early in the anthropoid lineage and subsequent effectively neutral fixation of repetitive DNA, rather than positive selection or unusual insertion pressures

Differential Contributions of Rare and Common, Coding and Noncoding Ret Mutations to Multifactorial Hirschsprung Disease Liability

The major gene for Hirschsprung disease (HSCR) encodes the receptor tyrosine kinase RET. In a study of 690 European- and 192 Chinese-descent probands and their parents or controls, we demonstrate the ubiquity of a >4-fold susceptibility from a C→T allele (rs2435357: p = 3.9 × 10−43 in European ancestry; p = 1.1 × 10−21 in Chinese samples) that probably arose once within the intronic RET enhancer MCS+9.7. With in vitro assays, we now show that the T variant disrupts a SOX10 binding site within MCS+9.7 that compromises RET transactivation. The T allele, with a control frequency of 20%–30%/47% and case frequency of 54%–62%/88% in European/Chinese-ancestry individuals, is involved in all forms of HSCR. It is marginally associated with proband gender (p = 0.13) and significantly so with length of aganglionosis (p = 7.6 × 10−5) and familiality (p = 6.2 × 10−4). The enhancer variant is more frequent in the common forms of male, short-segment, and simplex families whereas multiple, rare, coding mutations are the norm in the less common and more severe forms of female, long-segment, and multiplex families. The T variant also increases penetrance in patients with rare RET coding mutations. Thus, both rare and common mutations, individually and together, make contributions to the risk of HSCR. The distribution of RET variants in diverse HSCR patients suggests a “cellular-recessive” genetic model where both RET alleles' function is compromised. The RET allelic series, and its genotype-phenotype correlations, shows that success in variant identification in complex disorders may strongly depend on which patients are studied

A Global Declaration on Appropriate Use of Antimicrobial Agents across the Surgical Pathway

This declaration, signed by an interdisciplinary task force of 234 experts from 83 different countries with different backgrounds, highlights the threat posed by antimicrobial resistance and the need for appropriate use of antibiotic agents and antifungal agents in hospitals worldwide especially focusing on surgical infections. As such, it is our intent to raise awareness among healthcare workers and improve antimicrobial prescribing. To facilitate its dissemination, the declaration was translated in different languages