Recombination dynamics of a human Y-chromosomal palindrome:rapid GC-biased gene conversion, multi-kilobase conversion tracts, and rare inversions

The male-specific region of the human Y chromosome (MSY) includes eight large inverted repeats (palindromes) in which arm-to-arm similarity exceeds 99.9%, due to gene conversion activity. Here, we studied one of these palindromes, P6, in order to illuminate the dynamics of the gene conversion process. We genotyped ten paralogous sequence variants (PSVs) within the arms of P6 in 378 Y chromosomes whose evolutionary relationships within the SNP-defined Y phylogeny are known. This allowed the identification of 146 historical gene conversion events involving individual PSVs, occurring at a rate of 2.9-8.4×10(-4) events per generation. A consideration of the nature of nucleotide change and the ancestral state of each PSV showed that the conversion process was significantly biased towards the fixation of G or C nucleotides (GC-biased), and also towards the ancestral state. Determination of haplotypes by long-PCR allowed likely co-conversion of PSVs to be identified, and suggested that conversion tract lengths are large, with a mean of 2068 bp, and a maximum in excess of 9 kb. Despite the frequent formation of recombination intermediates implied by the rapid observed gene conversion activity, resolution via crossover is rare: only three inversions within P6 were detected in the sample. An analysis of chimpanzee and gorilla P6 orthologs showed that the ancestral state bias has existed in all three species, and comparison of human and chimpanzee sequences with the gorilla outgroup confirmed that GC bias of the conversion process has apparently been active in both the human and chimpanzee lineages

A computational framework for complex disease stratification from multiple large-scale datasets.

BACKGROUND: Multilevel data integration is becoming a major area of research in systems biology. Within this area, multi-'omics datasets on complex diseases are becoming more readily available and there is a need to set standards and good practices for integrated analysis of biological, clinical and environmental data. We present a framework to plan and generate single and multi-'omics signatures of disease states. METHODS: The framework is divided into four major steps: dataset subsetting, feature filtering, 'omics-based clustering and biomarker identification. RESULTS: We illustrate the usefulness of this framework by identifying potential patient clusters based on integrated multi-'omics signatures in a publicly available ovarian cystadenocarcinoma dataset. The analysis generated a higher number of stable and clinically relevant clusters than previously reported, and enabled the generation of predictive models of patient outcomes. CONCLUSIONS: This framework will help health researchers plan and perform multi-'omics big data analyses to generate hypotheses and make sense of their rich, diverse and ever growing datasets, to enable implementation of translational P4 medicine

Challenges in human genetic diversity: demographic history and adaption

Modern human genetic diversity is the result of demographic history, and selective effects that have acted to adapt different populations to their environments. Broad patterns of global diversity are well explained by geography, based on an out-of-Africa model of early human evolution. Genome-wide searches for signals of selection, plus studies of specific candidate loci and candidate phenotypes, have identified genes that show population differences due to adaptation to pathogens, climate, diet, and possibly cognitive challenges. Some past adaptations are now maladaptive, and can lead to disease. However, the history of adaptation is complex, and adaptive explanations are often unsupported by hard evidence

Shock velocity increase due to a heterogeneity produced by a two-gas layer

International audienceShock tube experiments are performed in order to study shock propagation along a two-gas layer in a confined geometry and to compare it to the case of a homogeneous density equivalent mixture. The analysis of the homogeneous case gives values for the adiabatic coefficient and density of the mixture of both gases, while the comparison between heterogeneous and homogeneous media with the same averaged density shows modifications of the shock front shape and velocity. In the two-gas layer, the shock propagates faster than in the homogeneous medium. The shock front is curved with a triple point which appears close to the shock-tube wall, in the slow medium, while it stays planar during its whole propagation in the homogeneous mixture. A correlation is found between the angle of curvature and the shock velocity increase. It is confirmed by two-dimensional Eulerian numerical calculations. Experiments and calculations exhibit very good agreement on all the measurements when molecular diffusion is taken into account in the numerical calculations. A sustained irregular refraction pattern of the shock front at the diffuse interface of both gases is obtained experimentally and confirmed by the calculations

Genetic signatures of coancestry within surnames

Surnames are cultural markers of shared ancestry within human populations. The Y chromosome, like many surnames, is paternally inherited, so men sharing surnames might be expected to share similar Y chromosomes as a signature of coancestry. Such a relationship could be used to connect branches of family trees [1], to validate population genetic studies based on isonymy [2], and to predict surname from crime-scene samples in forensics [3]. However, the link may be weak or absent due to multiple independent founders for many names, adoptions, name-changes and non-paternities, and mutation of Y haplotypes. Here, rather than focusing on a single name [4], we take a general approach by seeking evidence for a link in a sample of 150 randomly ascertained pairs of males who each share a British surname. We show that sharing a surname significantly elevates the probability of sharing a Y-chromosomal haplotype, and that this probability increases as surname frequency decreases. Within our sample, we estimate that up to 24% of pairs share recent ancestry and that a large surname-based forensic database might contribute to the intelligence-led investigation of up to ~70 rapes and murders per year in the UK. This approach would be applicable to any society using patrilineal surnames of reasonable time-depth

Recognition of gene conversion, co-conversion and inversion events.

<p>a) Existence of three genotypes at a hypothetical PSV indicates that gene conversion has taken place, if recurrent mutation is neglected. Genotyping the PSV in a phylogenetic context, and applying the principle of maximum parsimony, allows the recognition of: b) Haplogroup descending from an ancestor in which the PSV mutation has not yet arisen (G/G), and is therefore uninformative; c) Haplogroup descending from an ancestor in which the PSV mutation has arisen (G/A), but shows no variation, and therefore no evidence for gene conversion; d) Haplogroup descending from an ancestor in which the PSV mutation has arisen, and shows evidence of at least two bidirectional conversion events (G/G and A/A); e) Recognition of co-conversion of more than one PSV requires ‘phase’ information, as does (f) recognition of inversions.</p

Inter-specific sequence divergence in arms and spacers of palindrome P6.

a<p>2×2 contingency table, Chi-square test with Yates correction.</p

Schematic representation of the inversions identified within three haplogroups.

<p>The approximate position of each inversion is indicated by a red cross.</p