Epigenetics of aging.

The aging phenotype is the result of a complex interaction between genetic, epigenetic and environmental factors, and it is among the most complex phenotypes studied to date. Evidence suggests that epigenetic factors, including DNA methylation, histone modifications and microRNA expression, may affect the aging process and may be one of the central mechanisms by which aging predisposes to many age-related diseases. The total number of altered methylation sites increases with increasing age, such that they could serve as a biomarker for chronological age. This chapter summarizes the mechanisms by which these epigenetic factors contribute to aging and how they may affect the complex physiology of aging, lifespan and age-associated diseases.

Canonical WNT/ß-Catenin Signaling Activated by WNT9b and RSPO2 Cooperation Regulates Facial Morphogenesis in Mice.

The R-spondin (RSPO) family of proteins potentiate canonical WNT/ß-catenin signaling and may provide a mechanism to fine-tune the strength of canonical WNT signaling. Although several in vitro studies have clearly demonstrated the potentiation of canonical WNT signaling by RSPOs, whether this potentiation actually occurs in normal development and tissue function in vivo still remains poorly understood. Here, we provide clear evidence of the potentiation of canonical WNT signaling by RSPO during mouse facial development by analyzing compound Wnt9b and Rspo2 gene knockout mice and utilizing ex vivo facial explants. Wnt9b;Rspo2 double mutant mice display facial defects and dysregulated gene expression pattern that are significantly more severe than and different from those of Wnt9b or Rspo2 null mutant mice. Furthermore, we found suggestive evidence that the LGR4/5/6 family of the RSPO receptors may play less critical roles in WNT9b:RSPO2 cooperation. Our results suggest that RSPO-induced cooperation is a key mechanism for fine-tuning canonical WNT/ß-catenin signaling in mouse facial development.

The complex genetics of gait speed: genome-wide meta-analysis approach.

Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging.

Genotyping of geographically diverse Druze trios reveals substructure and a recent bottleneck.

Druze individuals rarely marry outside their faith (often practicing consanguinity) and are thus believed to form a genetic isolate. To comprehensively characterize the genetic structure of the Druze population, we recruited and genotyped 40 parent-offspring trios from the Upper Galilee in Israel and the Golan Heights, attempting to capture different extended families (clans) across various geographical locations. Principal component (PC) and ADMIXTURE analyses demonstrated that Druze are close to, yet distinct from, other Middle-Eastern groups (Bedouins and Palestinians), supporting the Druze's Middle-Eastern origin and their recent genetic isolation. Reconstruction of the Druze demographic history using identical-by-descent (IBD) segments suggested an ≈15-fold reduction in population size taking place ≈22-47 generations ago, close to the documented time of the foundation of the Druze faith at the 11th century. Combining the Galilee and Golan Druze genotypes with previously published data on Druze from the Carmel (Israel) and Lebanon demonstrated that all four Druze communities are genetically distinct. The Lebanese group shared less IBD segments (within the group and with other groups) compared with the Israeli Druze and showed higher heterozygosity (suggesting less consanguinity), but was less diverse in PC space. These findings suggest complex recent and ancient demographic history of the Druze population.

Sequencing an Ashkenazi reference panel supports population-targeted personal genomics and illuminates Jewish and European origins.

The Ashkenazi Jewish (AJ) population is a genetic isolate close to European and Middle Eastern groups, with genetic diversity patterns conducive to disease mapping. Here we report high-depth sequencing of 128 complete genomes of AJ controls. Compared with European samples, our AJ panel has 47% more novel variants per genome and is eightfold more effective at filtering benign variants out of AJ clinical genomes. Our panel improves imputation accuracy for AJ SNP arrays by 28%, and covers at least one haplotype in ≈ 67% of any AJ genome with long, identical-by-descent segments. Reconstruction of recent AJ history from such segments confirms a recent bottleneck of merely ≈ 350 individuals. Modelling of ancient histories for AJ and European populations using their joint allele frequency spectrum determines AJ to be an even admixture of European and likely Middle Eastern origins. We date the split between the two ancestral populations to ≈ 12-25 Kyr, suggesting a predominantly Near Eastern source for the repopulation of Europe after the Last Glacial Maximum.