Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

NOTCH1 mediates a switch between two distinct secretomes during senescence

Senescence, a persistent form of cell-cycle arrest, is often associated with a diverse secretome, which provides complex functionality for senescent cells within the tissue microenvironment. We show that oncogene-induced senescence is accompanied by a dynamic fluctuation of NOTCH1 activity, which drives a TGF-β-rich secretome, while suppressing the senescence-associated pro-inflammatory secretome through inhibition of C/EBPβ. NOTCH1 and NOTCH1-driven TGF-β contribute to 'lateral induction of senescence' through a juxtacrine NOTCH-JAG1 pathway. In addition, NOTCH1 inhibition during senescence facilitates upregulation of pro-inflammatory cytokines, promoting lymphocyte recruitment and senescence surveillance in vivo. As enforced activation of NOTCH1 signalling confers a near mutually exclusive secretory profile compared with typical senescence, our data collectively indicate that the dynamic alteration of NOTCH1 activity during senescence dictates a functional balance between these two distinct secretomes: one representing TGF-β and the other pro-inflammatory cytokines, highlighting that NOTCH1 is a temporospatial controller of secretome composition.This work was supported by the University of Cambridge, Cancer Research UK and Hutchison Whampoa. The M.N. laboratory is supported by Cancer Research UK Cambridge Institute Core Grant (C14303/A17197). M.H. was supported by CRUK Translational Medicine Research Fellowship and CRUK Clinician Scientist Fellowship (C52489/A19924). This work was also supported by a Wellcome Trust PRF (WT101835) to P.J.L., a Wellcome Trust Senior Fellowship to M.P.W. (108070/Z/15/Z), a Wellcome Trust Training Fellowship to N.J.M. (093964/Z/10/Z), and a Wellcome Trust Intermediate Fellowship (097162/Z/11/Z) to S.S. L.Z. was funded by the German Research Foundation (DFG; grants FOR2314 and SFB685), the Gottfried Wilhelm Leibniz Program, the European Research Council (projects ‘CholangioConcept’), the German Ministry for Education and Research (BMBF) (eMed-Multiscale HCC), the German Universities Excellence Initiative (third funding line: ‘future concept’), the German Center for Translational Cancer Research (DKTK) and the German–Israeli Cooperation in Cancer Research (DKFZ–MOST).This is the author accepted manuscript. The final version is available from Nature Publishing Group at http://dx.doi.org/10.1038/ncb3397

HLA-DQ haplotypes in 15 different populations

In order to understand the forces governing the evolution of the DQ molecule, PCR-based methods have been used to type the DQA1 and DQB1 loci encoding this heterodimer on 2,807 chromosomes from 15 different populations including Africans, Asians, Amerindians and Caucasians. These ethnically diverse samples represent a variety of population substructures and include small, isolated populations as well as larger populations where admixture has occurred. Nine DQA1 alleles and 18 DQB1 alleles have been identified which make up 42 distinct DQ haplotypes. Some haplotypes are found in all ethnic groups while others are confined to a single ethnic group or population. Despite evidence of recombination between the DQA1 and DQB1 loci, there are no examples of a haplotype carrying a DQw1-associated alpha chain and a DQw2-, DQw3-, or DQw4-associated beta chain in cis (and vice versa). These data suggest that these haplotypes, which encode unstable heterodimers, are rapidly removed from the population through natural selection

HLA-DQ haplotypes in 15 different populations

In order to understand the forces governing the evolution of the DQ molecule, PCR-based methods have been used to type the DQA1 and DQB1 loci encoding this heterodimer on 2,807 chromosomes from 15 different populations including Africans, Asians, Amerindians and Caucasians. These ethnically diverse samples represent a variety of population substructures and include small, isolated populations as well as larger populations where admixture has occurred. Nine DQA1 alleles and 18 DQB1 alleles have been identified which make up 42 distinct DQ haplotypes. Some haplotypes are found in all ethnic groups while others are confined to a single ethnic group or population. Despite evidence of recombination between the DQA1 and DQB1 loci, there are no examples of a haplotype carrying a DQw1-associated alpha chain and a DQw2-, DQw3-, or DQw4-associated beta chain in cis (and vice versa). These data suggest that these haplotypes, which encode unstable heterodimers, are rapidly removed from the population through natural selection

Genetic variability and linkage disequilibrium within the HLA-DP region: analysis of 15 different populations.

In order to understand the forces governing the evolution of the genetic diversity in the HLA-DP molecule, polymerase chain reaction (PCR)-based methods were used to characterize genetic variation at the DPA1 and DPB1 loci encoding this heterodimer on 2,807 chromosomes from 15 different populations including individuals of African, Asian, Amerindian, Indian and European origin. These ethnically diverse samples represent a variety of population substructures and include small, isolated populations as well as larger, presumably admixed populations. Ten DPA1 and 39 DPB1 alleles were identified and observed on 87 distinct DP haplotypes, 34 of which were found to be in significant positive linkage disequilibrium in at least one population. Some haplotypes were found in all ethnic groups while others were confined to a single ethnic group or population. Strong positive global linkage disequilibrium (Wn) between DPA1 and DPB1 was present in all 15 populations. The African populations displayed the lowest values of Wn whereas the Amerindian populations displayed near absolute disequilibrium. Analysis of the distribution of haplotypes using the normalized deviate of the Ewens-Watterson homozygosity statistic, F, suggests that DP haplotypes encoding the functional heterodimer are subject to much lower degrees of balancing selection than other loci within the HLA region. Finally, neighbor joining tree analyses demonstrate the power of haplotype diversity for inferring the relationships between the different populations