The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.

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Initial sequencing and analysis of the human genome.

抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Statistical method for testing the neutral mutation hypothesis by DNA polymorphism.

The lion's share of bacteria in various environments cannot be cloned in the laboratory and thus cannot be sequenced using existing technologies. A major goal of single-cell genomics is to complement gene-centric metagenomic data with whole-genome assemblies of uncultivated organisms. Assembly of single-cell data is challenging because of highly non-uniform read coverage as well as elevated levels of sequencing errors and chimeric reads. We describe SPAdes, a new assembler for both single-cell and standard (multicell) assembly, and demonstrate that it improves on the recently released E+V-SC assembler (specialized for single-cell data) and on popular assemblers Velvet and SoapDeNovo (for multicell data). SPAdes generates single-cell assemblies, providing information about genomes of uncultivatable bacteria that vastly exceeds what may be obtained via traditional metagenomics studies. SPAdes is available online ( http://bioinf.spbau.ru/spades ). It is distributed as open source software.

SPAdes, a new genome assembly algorithm and its applications to single-cell sequencing ( 7th Annual SFAF Meeting, 2012)

The sequence of the mouse genome is a key informational tool for understanding the contents of the human genome and a key experimental tool for biomedical research. Here, we report the results of an international collaboration to produce a high-quality draft sequence of the mouse genome. We also present an initial comparative analysis of the mouse and human genomes, describing some of the insights that can be gleaned from the two sequences. We discuss topics including the analysis of the evolutionary forces shaping the size, structure and sequence of the genomes; the conservation of large-scale synteny across most of the genomes; the much lower extent of sequence orthology covering less than half of the genomes; the proportions of the genomes under selection; the number of protein-coding genes; the expansion of gene families related to reproduction and immunity; the evolution of proteins; and the identification of intraspecies polymorphism.

/pdf/initial-sequencing-and-comparative-analysis-of-the-mouse-5a9n62pifj.pdf

Initial sequencing and comparative analysis of the mouse genome.

Where in genes do pathogenic mutations tend to occur and does this provide clues as to the possible underlying mechanisms by which single nucleotide polymorphisms (SNPs) cause disease? As splice-disrupting mutations tend to occur predominantly at exon ends, known also to be hot spots of cis-exonic splice control elements, we examine the relationship between the relative density of such exonic cis-motifs and pathogenic SNPs. In particular, we focus on the intragene distribution of exonic splicing enhancers (ESE) and the covariance between them and disease-associated SNPs. In addition to showing that disease-causing genes tend to be genes with a high intron density, consistent with missplicing, five factors established as trends in ESE usage, are considered: relative position in exons, relative position in genes, flanking intron size, splice sites usage, and phase. We find that more than 76% of pathogenic SNPs are within 3-69 bp of exon ends where ESEs generally reside, this being 13% more than expected. Overall from enrichment of pathogenic SNPs at exon ends, we estimate that approximately 20-45% of SNPs affect splicing. Importantly, we find that within genes pathogenic SNPs tend to occur in splicing-relevant regions with low ESE density: they are found to occur preferentially in the terminal half of genes, in exons flanked by short introns and at the ends of phase (0,0) exons with 3' non-"AGgt" splice site. We suggest the concept of the "fragile" exon, one home to pathogenic SNPs owing to its vulnerability to splice disruption owing to low ESE density.

/pdf/determinants-of-the-usage-of-splice-associated-cis-motifs-1y30am15yj.pdf

Determinants of the Usage of Splice-Associated cis-Motifs Predict the Distribution of Human Pathogenic SNPs

Why are short introns rarely a multiple of three nucleotides long? Why do essential genes cluster? Why are genes in operons often lined up in the order in which they are needed in the encoded pathway? In this Opinion article, we argue that these and many other - ostensibly disparate - observations are all pieces of an emerging picture in which multiple aspects of gene anatomy and genome architecture have evolved in response to error-prone gene expression.

/pdf/error-prevention-and-mitigation-as-forces-in-the-evolution-2aca9yhdkx.pdf

Error prevention and mitigation as forces in the evolution of genes and genomes.

What is the best way to teach evolution? As microevolution may be configured as a branch of genetics, it being a short conceptual leap from understanding the concepts of mutation and alleles (ie, genetics) to allele frequency change (ie, evolution), we hypothesised that learning genetics prior to evolution might improve student understanding of evolution In the UK, genetics and evolution are typically taught to 14- to 16-y-old secondary school students as separate topics with few links, in no particular order and sometimes with a large time span between Here, then, we report the results of a large trial into teaching order of evolution and genetics We modified extant questionnaires to ascertain students’ understanding of evolution and genetics along with acceptance of evolution Students were assessed prior to teaching, immediately post teaching and again after several months Teachers were not instructed what to teach, just to teach in a given order Regardless of order, teaching increased understanding and acceptance, with robust signs of longer-term retention Importantly, teaching genetics before teaching evolution has a significant (p < 0001) impact on improving evolution understanding by 7% in questionnaire scores beyond the increase seen for those taught in the inverse order For lower ability students, an improvement in evolution understanding was seen only if genetics was taught first Teaching genetics first additionally had positive effects on genetics understanding, by increasing knowledge These results suggest a simple, minimally disruptive, zero-cost intervention to improve evolution understanding: teach genetics first This same alteration does not, however, result in a significantly increased acceptance of evolution, which reflects a weak correlation between knowledge and acceptance of evolution Qualitative focus group data highlights the role of authority figures in determination of acceptance

/pdf/teaching-genetics-prior-to-teaching-evolution-improves-3aqddoam4f.pdf

Teaching genetics prior to teaching evolution improves evolution understanding but not acceptance.

Germline mutations in the FLCN gene cause Birt-Hogg-Dube syndrome, familial spontaneous pneumothorax, or apparently nonsyndromic inherited RCC. The vast majority of reported FLCN mutations are predicted to result in a truncated/absent gene product and so infrequent missense and inframe-deletion (IFD) FLCN mutations might indicate critical functional domains. To investigate this hypothesis we (1) undertook an in silico evolutionary analysis of the FLCN sequence and (2) investigated in vitro the functional effects of naturally occurring FLCN missense/IFD mutations. The folliculin protein sequence evolved more slowly and was under stronger purifying selection than the average gene, most notably at a region between codons 100 and 230. Pathogenic missense and IFD FLCN mutations that impaired folliculin tumor suppressor function significantly disrupted the stability of the FLCN gene product but two missense substitutions initially considered to be putative mutations did not impair protein stability, growth suppression activity, or intracellular localization of folliculin. These findings are consistent with the distribution of FLCN mutations throughout the coding sequence, and suggest that multiple protein domains contribute to folliculin stability and tumor suppressor activity. In vitro assessment of protein stability and tumor suppressor activity provides a practical strategy for assessing the pathogenicity of potential FLCN mutations.

Birt Hogg‐Dubé syndrome‐associated FLCN mutations disrupt protein stability

Although both genotypes with elevated mutation rate (mutators) and mobilization of insertion sequence (IS) elements have substantial impact on genome diversification, their potential interactions are unknown. Moreover, the evolutionary forces driving gradual accumulation of these elements are unclear: Do these elements spread in an initially transposon-free bacterial genome as they enable rapid adaptive evolution? To address these issues, we inserted an active IS1 element into a reduced Escherichia coli genome devoid of all other mobile DNA. Evolutionary laboratory experiments revealed that IS elements increase mutational supply and occasionally generate variants with especially large phenotypic effects. However, their impact on adaptive evolution is small compared with mismatch repair mutator alleles, and hence, the latter impede the spread of IS-carrying strains. Given their ubiquity in natural populations, such mutator alleles could limit early phase of IS element evolution in a new bacterial host. More generally, our work demonstrates the existence of an evolutionary conflict between mutation-promoting mechanisms.

/pdf/competition-between-transposable-elements-and-mutator-genes-dn4xuehsi9.pdf

Laurence D. Hurst

Papers

Determinants of the Usage of Splice-Associated cis-Motifs Predict the Distribution of Human Pathogenic SNPs

Error prevention and mitigation as forces in the evolution of genes and genomes.

Teaching genetics prior to teaching evolution improves evolution understanding but not acceptance.

Birt Hogg‐Dubé syndrome‐associated FLCN mutations disrupt protein stability

Competition between Transposable Elements and Mutator Genes in Bacteria