Problems in Population Genetics

群体遗传学问题

• 批准号: 0107420
• 负责人: Stanley Sawyer
• 金额: --
• 依托单位: Washington University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0107420&HistoricalAwards=false
• 关键词: Problems; Population; Genetics

Sawyer0107420 The investigator studies ways to estimate the average amountof selection for or against new mutations at a particular geneticlocus using information contained in aligned DNA or proteinsequences. If the estimated amount of selection is significantlynegative, this is an indication that the region is understabilizing selection and may have an important biologicalfunction. If the estimated average amount of selection ispositive, then new variants in this region are favored, as iscommon for some immune system genes. Models that allow randomvariation of the amounts of selection over sites are alsoconsidered. The methods studied are computationally easy to carryout and have easily obtained significance levels, but assumestatistical independence between polymorphic sites instead of themore usual assumption of tight linkage. Studies have shown inmany cases that short-segment gene conversion and recombinationact at a greater rate than point mutation, so that tight linkageis not always a reasonable assumption. Simulations are carriedout to test the assumption that small to moderate amounts of geneconversion and recombination are sufficient to guarantee enoughindependence between sites so that the proposed estimators willhave desirable statistical properties. The models are applied toaligned sequences from public databases. They are also applied tohuman SNP datasets, for which the assumption of sitewiseindependence is clearer. Recent advances in biology have made a vast amount of dataavailable about the human genome and about the genomes of otherspecies. Tools for understanding the significance of this data,and in particular the significance of variation in this databetween individuals, have lagged behind. One question is whethernew genetic variants at a particular genetic locus (or segment ofDNA) have been favored on the average in the past, have renderedtheir owners less fit, or have had essentially the same effect onthe fate of individuals with those DNA variants. Tests areproposed that give a computationally easy way of determiningwhich of these three cases applies at a particular genetic locus.These tests are based on the configurations of variant sites inDNA from several individuals at that locus. The results of thistest can give information about the function of this stretch ofDNA. They can also give information about how a particular geneis affected by or is currently being affected by evolution.Information from related biological species can give furtherinformation. The difficulty of the proposed methods is that theyassume that different portions of the genetic locus are evolvingapproximately independently. For some genetic data (for example,SNP for "single-nucleotide polymorphism" data) this can generallybe assumed. The sensitivity of the proposed methods to thisindependence assumption for non-SNP data is tested.

研究者研究的方法是利用包含在对齐的DNA或蛋白质序列中的信息来估计在特定遗传位点上选择或反对新突变的平均数量。如果估计的选择量明显为负，这表明该区域选择不稳定，可能具有重要的生物学功能。如果估计的平均选择量是阳性的，那么这个区域的新变体就更受青睐，就像某些免疫系统基因一样。还考虑了允许在站点上选择数量随机变化的模型。所研究的方法在计算上易于执行，并且容易获得显著性水平，但假设多态性位点之间的统计独立性，而不是更常见的紧密连锁假设。研究表明，在许多情况下，短片段基因转换和重组比点突变的速度更快，因此紧密联系并不总是一个合理的假设。进行模拟以测试假设，即少量到中等数量的基因转换和重组足以保证位点之间的足够独立性，从而使所提出的估计器具有理想的统计特性。该模型应用于来自公共数据库的序列比对。它们也被应用于人类SNP数据集，其站点独立性的假设更为清晰。生物学的最新进展使大量关于人类基因组和其他物种基因组的数据成为可能。理解这些数据的重要性的工具，特别是个体之间数据差异的重要性，已经落后了。其中一个问题是，某个特定基因位点（或DNA片段）的新基因变异是否在过去的平均水平上更受青睐，是否使其所有者更不适合，或者是否对具有这些DNA变异的个体的命运产生了本质上相同的影响。提出了一种计算简便的方法来确定这三种情况中的哪一种适用于特定的遗传位点。这些检测是基于来自该位点的几个个体的dna变异位点的结构。这个测试的结果可以提供有关这段dna功能的信息。它们还可以提供有关特定基因如何受到进化影响或目前正在受到进化影响的信息。来自相关生物物种的信息可以提供进一步的信息。所提出的方法的困难之处在于，它们假设遗传位点的不同部分大约独立地进化。对于某些遗传数据（例如，SNP表示“单核苷酸多态性”数据），通常可以这样假设。对于非snp数据，所提出的方法对这种独立性假设的敏感性进行了测试。