The global burden of cancer continues to increase largely because of the aging and growth of the world population alongside an increasing adoption of cancer-causing behaviors, particularly smoking, in economically developing countries. Based on the GLOBOCAN 2008 estimates, about 12.7 million cancer cases and 7.6 million cancer deaths are estimated to have occurred in 2008; of these, 56% of the cases and 64% of the deaths occurred in the economically developing world. Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females, accounting for 23% of the total cancer cases and 14% of the cancer deaths. Lung cancer is the leading cancer site in males, comprising 17% of the total new cancer cases and 23% of the total cancer deaths. Breast cancer is now also the leading cause of cancer death among females in economically developing countries, a shift from the previous decade during which the most common cause of cancer death was cervical cancer. Further, the mortality burden for lung cancer among females in developing countries is as high as the burden for cervical cancer, with each accounting for 11% of the total female cancer deaths. Although overall cancer incidence rates in the developing world are half those seen in the developed world in both sexes, the overall cancer mortality rates are generally similar. Cancer survival tends to be poorer in developing countries, most likely because of a combination of a late stage at diagnosis and limited access to timely and standard treatment. A substantial proportion of the worldwide burden of cancer could be prevented through the application of existing cancer control knowledge and by implementing programs for tobacco control, vaccination (for liver and cervical cancers), and early detection and treatment, as well as public health campaigns promoting physical activity and a healthier dietary intake. Clinicians, public health professionals, and policy makers can play an active role in accelerating the application of such interventions globally.

/pdf/global-cancer-statistics-49zjx478re.pdf

Global cancer statistics

Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis.

http://ibgwww.colorado.edu/cdrom2009/ScriptsA/purcell/GWAS/boulder_09_plink_intro.pdf

PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage Analyses

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.

/pdf/initial-sequencing-and-analysis-of-the-human-genome-5dapk1rsx1.pdf

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

Summary: Research over the last few years has revealed significant haplotype structure in the human genome. The characterization of these patterns, particularly in the context of medical genetic association studies, is becoming a routine research activity. Haploview is a software package that provides computation of linkage disequilibrium statistics and population haplotype patterns from primary genotype data in a visually appealing and interactive interface.

Availability: http://www.broad.mit.edu/mpg/haploview/

Contact: jcbarret@broad.mit.edu

/pdf/haploview-analysis-and-visualization-of-ld-and-haplotype-1p9iyir38a.pdf

Haploview: analysis and visualization of LD and haplotype maps

Identifying regions of the genome that are depleted of mutations can reveal potentially deleterious variants. Short tandem repeats (STRs), comprised of repeating motifs of 1-6bp, are among the largest contributors of de novo mutations in humans and are implicated in a variety of human disorders. However, because of the challenges STRs pose to bioinformatics tools, studies of STR mutations have been limited to highly ascertained panels of several dozen loci. Here, we harnessed novel bioinformatics tools and an analytical framework to estimate mutation parameters at each STR in the human genome. We then developed a model of the STR mutation process that allows us to obtain accurate estimates of mutation parameters at each STR by correlating genotypes with local sequence heterozygosity. Finally, we applied our method to obtain robust estimates of the impact of local sequence features on mutation parameters and used this to create a framework for measuring constraint at STRs by comparing observed vs. expected mutation rates. Constraint scores identified known pathogenic variants with early onset effects. Our constraint metrics will provide a valuable tool for prioritizing pathogenic STRs in medical genetics studies.

/pdf/a-framework-to-interpret-short-tandem-repeat-variation-in-1lthptu6ww.pdf

A framework to interpret short tandem repeat variation in humans

Mutations occur at vastly different rates across the genome, and between populations. Here, we measure variation in the mutational spectrum in a sample of human genomes representing all major world populations. We find at least two distinct signatures of variation. One, private to certain Native American populations, is novel and is concentrated at CpG sites. The other is consistent with a previously reported signature characterized by TCC>TTC mutations in Europeans and other West Eurasians. We describe the geographic extent of this signature and show that it is detectable in the genomes of ancient, but not archaic humans. We hypothesize that these two signatures are driven by independent processes and both result from differences in either the rate, or repair efficiency, of damage due to deamination of methylated bases - respectively guanine and cytosine for the two processes. Variation in these processes could be due to environmental, genetic, or life-history variation between populations, and dramatically affects the spectrum of rare variation in different populations.

/pdf/variation-in-mutation-rates-among-human-populations-4mlh46aq72.pdf

Variation in mutation rates among human populations

Transcranial Doppler ultrasonography: what is its role in cardiac and vascular surgical patients?

Ancient DNA has revolutionized our understanding of human population history. However, its potential to examine how rapid cultural evolution to new lifestyles may have driven biological adaptation has not been met, largely due to limited sample sizes. We assembled genome-wide data from 1,291 individuals from Europe over 10,000 years, providing a dataset that is large enough to resolve the timing of selection into the Neolithic, Bronze Age, and Historical periods. We identified 25 genetic loci with rapid changes in frequency during these periods, a majority of which were previously undetected. Signals specific to the Neolithic transition are associated with body weight, diet, and lipid metabolism-related phenotypes. They also include immune phenotypes, most notably a locus that confers immunity to Salmonella infection at a time when ancient Salmonella genomes have been shown to adapt to human hosts, thus providing a possible example of human-pathogen co-evolution. In the Bronze Age, selection signals are enriched near genes involved in pigmentation and immune-related traits, including at a key human protein interactor of SARS-CoV-2. Only in the Historical period do the selection candidates we detect largely mirror previously-reported signals, highlighting how the statistical power of previous studies was limited to the last few millennia. The Historical period also has multiple signals associated with vitamin D binding, providing evidence that lactase persistence may have been part of an oligogenic adaptation for efficient calcium uptake and challenging the theory that its adaptive value lies only in facilitating caloric supplementation during times of scarcity. Finally, we detect selection on complex traits in all three periods, including selection favoring variants that reduce body weight in the Neolithic. In the Historical period, we detect selection favoring variants that increase risk for cardiovascular disease plausibly reflecting selection for a more active inflammatory response that would have been adaptive in the face of increased infectious disease exposure. Our results provide an evolutionary rationale for the high prevalence of these deadly diseases in modern societies today and highlight the unique power of ancient DNA in elucidating biological change that accompanied the profound cultural transformations of recent human history.

/pdf/1000-ancient-genomes-uncover-10000-years-of-natural-2u00aeqi.pdf

1,000 ancient genomes uncover 10,000 years of natural selection in Europe

Erratum: Presynaptic A1-purinoceptor-mediated inhibitory effects of adenosine and its stable analogues on the mouse hemidiaphragm preparation (Naunyn-Schmiedeberg's Arch Pharmacol (1992) 346:197-202)

David Reich

Papers

A framework to interpret short tandem repeat variation in humans

Variation in mutation rates among human populations

Transcranial Doppler ultrasonography: what is its role in cardiac and vascular surgical patients?

1,000 ancient genomes uncover 10,000 years of natural selection in Europe

Erratum: Presynaptic A1-purinoceptor-mediated inhibitory effects of adenosine and its stable analogues on the mouse hemidiaphragm preparation (Naunyn-Schmiedeberg's Arch Pharmacol (1992) 346:197-202)