Modeling the effects of consanguinity on autosomal and X-chromosomal runs of homozygosity and identity-by-descent sharing.

Runs of homozygosity (ROH) and identity-by-descent (IBD) sharing can be studied in diploid coalescent models by noting that ROH and IBD-sharing at a genomic site are predicted to be inversely related to coalescence times-which in turn can be mathematically obtained in terms of parameters describing consanguinity rates. Comparing autosomal and X-chromosomal coalescent models, we consider ROH and IBD-sharing in relation to consanguinity that proceeds via multiple forms of first-cousin mating. We predict that across populations with different levels of consanguinity, (1) in a manner that is qualitatively parallel to the increase of autosomal IBD-sharing with autosomal ROH, X-chromosomal IBD-sharing increases with X-chromosomal ROH, owing to the dependence of both quantities on consanguinity levels; (2) even in the absence of consanguinity, X-chromosomal ROH and IBD-sharing levels exceed corresponding values for the autosomes, owing to the smaller population size and lower coalescence time for the X chromosome than for autosomes; (3) with matrilateral consanguinity, the relative increase in ROH and IBD-sharing on the X chromosome compared to the autosomes is greater than in the absence of consanguinity. Examining genome-wide SNPs in human populations for which consanguinity levels have been estimated, we find that autosomal and X-chromosomal ROH and IBD-sharing levels generally accord with the predictions. We find that each 1% increase in autosomal ROH is associated with an increase of 2.1% in X-chromosomal ROH, and each 1% increase in autosomal IBD-sharing is associated with an increase of 1.6% in X-chromosomal IBD-sharing. For each calculation, particularly for ROH, the estimate is reasonably close to the increase of 2% predicted by the population-size difference between autosomes and X chromosomes. The results support the utility of coalescent models for understanding patterns of genomic sharing and their dependence on sex-biased processes.

Long-term ecological and evolutionary dynamics in the gut microbiomes of carbapenemase-producing Enterobacteriaceae colonized subjects.

Long-term colonization of the gut microbiome by carbapenemase-producing Enterobacteriaceae (CPE) is a growing area of public health concern as it can lead to community transmission and rapid increase in cases of life-threatening CPE infections. Here, leveraging the observation that many subjects are decolonized without interventions within a year, we used longitudinal shotgun metagenomics (up to 12 timepoints) for detailed characterization of ecological and evolutionary dynamics in the gut microbiome of a cohort of CPE-colonized subjects and family members (n = 46; 361 samples). Subjects who underwent decolonization exhibited a distinct ecological shift marked by recovery of microbial diversity, key commensals and anti-inflammatory pathways. In addition, colonization was marked by elevated but unstable Enterobacteriaceae abundances, which exhibited distinct strain-level dynamics for different species (Escherichia coli and Klebsiella pneumoniae). Finally, comparative analysis with whole-genome sequencing data from CPE isolates (n = 159) helped identify substrain variation in key functional genes and the presence of highly similar E. coli and K. pneumoniae strains with variable resistance profiles and plasmid sharing. These results provide an enhanced view into how colonization by multi-drug-resistant bacteria associates with altered gut ecology and can enable transfer of resistance genes, even in the absence of overt infection and antibiotic usage.

Recent Evolutionary History of Tigers Highlights Contrasting Roles of Genetic Drift and Selection.

Species conservation can be improved by knowledge of evolutionary and genetic history. Tigers are among the most charismatic of endangered species and garner significant conservation attention. However, their evolutionary history and genomic variation remain poorly known, especially for Indian tigers. With 70% of the world's wild tigers living in India, such knowledge is critical. We re-sequenced 65 individual tiger genomes representing most extant subspecies with a specific focus on tigers from India. As suggested by earlier studies, we found strong genetic differentiation between the putative tiger subspecies. Despite high total genomic diversity in India, individual tigers host longer runs of homozygosity, potentially suggesting recent inbreeding or founding events, possibly due to small and fragmented protected areas. We suggest the impacts of ongoing connectivity loss on inbreeding and persistence of Indian tigers be closely monitored. Surprisingly, demographic models suggest recent divergence (within the last 20,000 years) between subspecies and strong population bottlenecks. Amur tiger genomes revealed the strongest signals of selection related to metabolic adaptation to cold, whereas Sumatran tigers show evidence of weak selection for genes involved in body size regulation. We recommend detailed investigation of local adaptation in Amur and Sumatran tigers prior to initiating genetic rescue.

Mathematical Properties of Linkage Disequilibrium Statistics Defined by Normalization of the Coefficient D = pAB - pApB.

BACKGROUND: Many statistics for measuring linkage disequilibrium (LD) take the form of a normalization of the LD coefficient D. Different normalizations produce statistics with different ranges, interpretations, and arguments favoring their use. METHODS: Here, to compare the mathematical properties of these normalizations, we consider 5 of these normalized statistics, describing their upper bounds, the mean values of their maxima over the set of possible allele frequency pairs, and the size of the allele frequency regions accessible given specified values of the statistics. RESULTS: We produce detailed characterizations of these properties for the statistics d and ρ, analogous to computations previously performed for r2. We examine the relationships among the statistics, uncovering conditions under which some of them have close connections. CONCLUSION: The results contribute insight into LD measurement, particularly the understanding of differences in the features of different LD measures when computed on the same data.

Consanguinity Rates Predict Long Runs of Homozygosity in Jewish Populations.

OBJECTIVES: Recent studies have highlighted the potential of analyses of genomic sharing to produce insight into the demographic processes affecting human populations. We study runs of homozygosity (ROH) in 18 Jewish populations, examining these groups in relation to 123 non-Jewish populations sampled worldwide. METHODS: By sorting ROH into 3 length classes (short, intermediate, and long), we evaluate the impact of demographic processes on genomic patterns in Jewish populations. RESULTS: We find that the portion of the genome appearing in long ROH - the length class most directly related to recent consanguinity - closely accords with data gathered from interviews during the 1950s on frequencies of consanguineous unions in various Jewish groups. CONCLUSION: The high correlation between 1950s consanguinity levels and coverage by long ROH explains differences across populations in ROH patterns. The dissection of ROH into length classes and the comparison to consanguinity data assist in understanding a number of additional phenomena, including similarities of Jewish populations to Middle Eastern, European, and Central and South Asian non-Jewish populations in short ROH patterns, relative lengths of identity-by-descent tracts in different Jewish groups, and the "population isolate" status of the Ashkenazi Jews.

Genetic Diversity and Societally Important Disparities.

The magnitude of genetic diversity within human populations varies in a way that reflects the sequence of migrations by which people spread throughout the world. Beyond its use in human evolutionary genetics, worldwide variation in genetic diversity sometimes can interact with social processes to produce differences among populations in their relationship to modern societal problems. We review the consequences of genetic diversity differences in the settings of familial identification in forensic genetic testing, match probabilities in bone marrow transplantation, and representation in genome-wide association studies of disease. In each of these three cases, the contribution of genetic diversity to social differences follows from population-genetic principles. For a fourth setting that is not similarly grounded, we reanalyze with expanded genetic data a report that genetic diversity differences influence global patterns of human economic development, finding no support for the claim. The four examples describe a limit to the importance of genetic diversity for explaining societal differences while illustrating a distinction that certain biologically based scenarios do require consideration of genetic diversity for solving problems to which populations have been differentially predisposed by the unique history of human migrations.

Choosing Subsamples for Sequencing Studies by Minimizing the Average Distance to the Closest Leaf.

Imputation of genotypes in a study sample can make use of sequenced or densely genotyped external reference panels consisting of individuals that are not from the study sample. It also can employ internal reference panels, incorporating a subset of individuals from the study sample itself. Internal panels offer an advantage over external panels because they can reduce imputation errors arising from genetic dissimilarity between a population of interest and a second, distinct population from which the external reference panel has been constructed. As the cost of next-generation sequencing decreases, internal reference panel selection is becoming increasingly feasible. However, it is not clear how best to select individuals to include in such panels. We introduce a new method for selecting an internal reference panel--minimizing the average distance to the closest leaf (ADCL)--and compare its performance relative to an earlier algorithm: maximizing phylogenetic diversity (PD). Employing both simulated data and sequences from the 1000 Genomes Project, we show that ADCL provides a significant improvement in imputation accuracy, especially for imputation of sites with low-frequency alleles. This improvement in imputation accuracy is robust to changes in reference panel size, marker density, and length of the imputation target region.