The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.

https://cdr.lib.unc.edu/downloads/v692t8920

A global reference for human genetic variation.

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Integrative analysis of 111 reference human epigenomes

Copy number variation (CNV) of DNA sequences is functionally significant but has yet to be fully ascertained. We have constructed a first-generation CNV map of the human genome through the study of 270 individuals from four populations with ancestry in Europe, Africa or Asia (the HapMap collection). DNA from these individuals was screened for CNV using two complementary technologies: single-nucleotide polymorphism (SNP) genotyping arrays, and clone-based comparative genomic hybridization. A total of 1,447 copy number variable regions (CNVRs), which can encompass overlapping or adjacent gains or losses, covering 360 megabases (12% of the genome) were identified in these populations. These CNVRs contained hundreds of genes, disease loci, functional elements and segmental duplications. Notably, the CNVRs encompassed more nucleotide content per genome than SNPs, underscoring the importance of CNV in genetic diversity and evolution. The data obtained delineate linkage disequilibrium patterns for many CNVs, and reveal marked variation in copy number among populations. We also demonstrate the utility of this resource for genetic disease studies.

https://hal.archives-ouvertes.fr/hal-03378416/document

Global variation in copy number in the human genome

Theory and data suggest that a male in good condition at the end of the period of parental investment is expected to outreproduce a sister in similar condition, while she is expected to outreproduce him if both are in poor condition. Accordingly, natural selection should favor parental ability to adjust the sex ratio of offspring produced according to parental ability to invest. Data from mammals support the model: As maternal condition declines, the adult female tends to produce a lower ratio of males to females.

https://science.sciencemag.org/content/sci/179/4068/90.full.pdf

Natural selection of parental ability to vary the sex ratio of offspring.

Since the completion of the human genome project in 2003, extraordinary progress has been made in genome sequencing technologies, which has led to a decreased cost per megabase and an increase in the number and diversity of sequenced genomes. An astonishing complexity of genome architecture has been revealed, bringing these sequencing technologies to even greater advancements. Some approaches maximize the number of bases sequenced in the least amount of time, generating a wealth of data that can be used to understand increasingly complex phenotypes. Alternatively, other approaches now aim to sequence longer contiguous pieces of DNA, which are essential for resolving structurally complex regions. These and other strategies are providing researchers and clinicians a variety of tools to probe genomes in greater depth, leading to an enhanced understanding of how genome sequence variants underlie phenotype and disease.

Coming of age: ten years of next-generation sequencing technologies

Alport's syndrome continues to pose many challenges to the geneticist. In the 1960s and 1970s controversy surrounded the pattern of inheritance, but studies then were complicated and confused by the lack of clear clinical diagnostic criteria on which to make a diagnosis. Families with a variety of hereditary nephritides following all Mendelian patterns of inheritance were loosely grouped together under the eponym Alport's syndrome. In the 1980s a strict set of diagnostic criteria was established which enabled the identification of a clinically homogeneous group of families [3]. DNA linkage studies on these families demonstrated linkage to markers on the long arm of the X chromosome, and in 1990 a novel collagen gene (COL4A5), mapping to the same area, was cloned [4] which became the candidate gene for Alport's syndrome. The first few mutations to be described in COL4A5 were shown in several cases to segregate together with the disease in several families [1, 2], and considerable optimism was expressed for rapid progress from that point. The challenge has proved greater than was anticipated originally. COL4A5 is a large gene (approximately 240 kb), with 51 exons, and every affected family appears to have a unique mutation. Mutations described to date range from large deletions of 450 kb of DNA to single base changes, at the other end of the spectrum. So far, no genotype:phenotype correlation has emerged, and initial suggestions that large deletions may have a greater chance of being associated with the development of anti-GBM antibodies after renal transplantation have not been substantiated. We have screened DNA from 60 unrelated individuals with 'classic' Alport's syndrome and defined mutations in COL4A5 in 20. In two families we have offered carrier testing to the pregnant sisters of affected males, and in a third family we performed diagnostic molecular tests on two young boys with unexplained haematuria who were distantly related to a male with Alport's syndrome in whom the mutation was known. Despite extensive molecular studies by several groups the combined experience internationally is that mutations in

Genetic aspects of renal dysfunction: Alport's syndrome

Techniques havebeenreported inwhich fluorescence insituhybridisation (FISH) andcosmidprobesareusedtodetect trisomy21 (andotherabnormalities involving chromosomesX,Y,13,and18) onuncultured amniocytes. Howeverthe detection rateoftrisomy 21islowerthan fortheotheranomalies owingtoalarger number ofuninformative results and false negatives. We reportthesimultaneous useoftwo differentially labelled cosmidcontigs to improvethedetection rateoftrisomy21 on uncultured amniocytesamplesthus allowing theprenatal diagnosis ofDown's syndrome evenifonlyfewlabelled nuclei areavailable.

Martin Bobrow

Papers

Genetic aspects of renal dysfunction: Alport's syndrome

FISHdetection oftrisomy 21ininterphase by thesimultaneous useoftwodifferentially labelled cosmid contigs

Fertility inamalewithtrisomy 21