基因进化的同义与非同义替代计算及统计检验的比较分析

基因氨基酸编码区的核苷酸具有不同替代速率.同义替代不引起氨基酸改变,它们基本是中性替代速率;非同义替代引起氨基酸变化,替代速率常常比同义替代速率低. 非同义(或同义)替代速率定义为单位时间(如1年)内或者一个世代内1个非同义(或同义)位点上发生替代的数目,用符号dN(或dS)来表示. 生物体内发生的非同义突变大多数属于有害突变,只有少数是中性突变或有利突变. 对有害的非同义突变来说,dN-dS＜1;而对于有利的非同义突变来说,dN-dS＞1. 仅仅通过比较dN和dS还不能确定是否就一定受到选择作用,还必须用统计学的方法来检验它们的真实性和可靠性. 计算dN和dS的方法有多种,常见的是4种:N-G模型、改进的N-G模型、Li-Wu-Luo模型和P-B-Li模型.4种方法从不同的角度计算编码区核苷酸的dN,dS值,它们各有特点,适合不同基因的计算.对dN,dS值进行统计检验的方法也有多种,常见的方法有5种:Z检验、Tajima‘s D 检验、Fu and Li检验、HKA检验和MK检验.这5种检验方法也各有特点,适合不同基因dN,dS值的检验.     

SARS冠状病毒的起源和进化初探

发展了一种研究基因序列进化的随机替代模型,根据一组从某个最近共同祖先演化而来的若干序列,可以预测此共同祖先序列,并计算随机替代概率矩阵,确定了从祖先序列的各个碱基到进化序列的各个碱基之间的替代概率。将这一模型应用于分析包括SARS冠状病毒在内的4种冠状病毒全基因组的演化规律,确定了在若干较保守的编码蛋白基因序列中同义替代位点的最近共同祖先序列以及分歧进化后的累计同义替代数目。结果表明,SARS病毒和其他几种已知的冠状病毒具有相当的进化历程,但存在不同的进化途径,支持了SARS病毒在造成此次大规模感染人体之前已经历了较长的进化历程的猜测。     

大肠杆菌的同义密码子使用偏性对蛋白质折叠速率的影响

考虑到同义密码子使用偏性的物种差异性,选取大肠杆菌的54条核蛋白为研究对象,将每条核蛋白按二级结构截取出α螺旋片段、β折叠片段和无规卷曲(α-β混合)片段,然后找到每个片段相关的核酸序列信息,计算其同义密码子使用度和相应肽链的折叠速率.在此基础上,分析了同义密码子使用偏性和相应肽链折叠速率之间的相关性,发现对于不同二级结构类的肽链片段,都有部分密码子的使用偏性与其对应的肽链折叠速率显著相关.因此,在蛋白质折叠中,同义密码子的使用偏性起着重要作用.     

基因进化过程中核苷酸替代模型的比较分析

DNA序列中核苷酸替代数的估计是测定基因间进化距离的数学统计方法,是研究基因进化的基础.由于DNA分子包含多种序列区域等原因,核苷酸序列的替代模式比较复杂.最基本的核苷酸序列替代模型是p-距离模型J、ukes-Cantor模型、Kimura两参数模型.在此基础上衍生出其它一系列模型,如Tajima-Nei模型、Tamura模型、Tamura-Nei模型等.这些数学模型在拟合DNA序列进化的真实度时各有特点.这些模型中都假定各个位点的核苷酸替代速率一致,但实际情况并非完全如此,而是核苷酸的替代速率近似地遵循Г分布.     

玉米同义密码子分析

利用现有的玉米基因组数据库数据,使用Codon w软件对筛选得到的29657个有效基因进行同义密码子使用的多变量分析.结果表明:在玉米中发现23个最优密码子,并且密码子第3位碱基呈现出明显的GC偏性.表明基因的GC含量直接影响玉米的密码子使用频率,同时片段长度越短,其最优密码子的使用频率越高.23个最优密码子的确定对玉米的基因改造和基因育种提供了重要的参考依据.     

非同义单核苷酸变异致病性预测研究综述

超过6000种人类疾病是由非同义单核苷酸变异(Non-synonymous single nucleotide variations,nsSNVs)引发的,快速准确地预测nsSNVs的致病性,有助于理解发病原理和设计新药物,也是生物信息领域的重要研究课题之一.该文给出了nsSNVs致病性研究的重要意义与背景知识;总结了...     

被子植物SQUA类基因适应性进化的统计检测

SQUAMOSA(SQUA)类基因是MADS-box基因家族中参与花被发生发育的重要基因.测定了麻竹的SQUA基因序列并分析了被子植物中SQUA类基因的系统发育式样;采用相对速率检验、同义与非同义置换位点统计以及似然比检验方法,分析了单子叶和真双子叶植物最近共同祖先中SQUA基因发生基因重复后的进化速率与适应机制.结果表明:真双子叶植物分支中SQUA类基因的相对速率和同义与非同义置换位点均显著高于单子叶植物分支;同时, dN/dS值表明真双子叶植物分支中可能存在正选择压力.     

科学家发现可能决定人类大脑进化的基因

8月16日,一个国际科学家小组宣称他们发现了人类与黑猩猩的祖先“分家”以来变化最快的一个基因。科学家称,这个基因很可能是人类大脑进化的关键基因。美国、比利时和法国科学家组成的这个研究小组应用计算机对人类、黑猩猩以及其他脊椎动物进行广泛的全基因组比较之后发现了这个基因。他们的研     

《科学》评出2005年十大科学进展

美国《科学》杂志评出2005年十大科学进展,进化研究名列首位。《科学》杂志强调,达尔文提出进化论已快一个半世纪,但科学家还能揭示出生物进化新的细节,表明进化研究仍具有现实意义。黑猩猩基因组图谱于2005年10月公布,人类基因组的单核苷酸变异图谱也随后发表。这两份图谱的深入比较不仅会揭示人类进化的过程,也为艾滋病、心脏病等疾病的研究提供了材料,有望为未来的“个性化基因医疗”奠定基础。 2005年科学家还再造了1981年“西班牙流感”病毒并测定其基因序列,发现     

线虫DNA序列沿染色体进化的非均匀性

选择了四个信息参量来刻画核酸序列的进化水平,研究线虫染色体全序列、基因序列和基因间序列的进化水平沿染色体的非均匀分布规律.结果显示各类序列的进化水平沿常染色体呈现明显的非均匀性和规律性.进化水平高的序列分布在染色体的两端,是进化活跃区,进化水平低的序列,分布在染色体的中部,是进化保守区;基因序列和基因间序列是协同进化的,在染色体上具有相同的分布规律;Ⅳ号染色体显示出了染色体形成的拼接模式,由此推断常染色体的形成与进化过程是先以一个进化保守序列为核序列,在其两端拼接其它的序列,通过序列间的协调和融合使之逐渐走向成熟;整个X染色体具有稳定的进化水平,进化模式与常染色体不同.     

Unexpectedly similar rates of nucleotide substitution found in male and female hominids

In 1947, it was suggested that, in humans, the mutation rate is dramatically higher in the male germ line than in the female germ line. This hypothesis has been supported by the observation that, among primates, Y-linked genes evolved more rapidly than homologous X-linked genes. Based on these evolutionary studies, the ratio (alpha(m)) of male to female mutation rates in primates was estimated to be about 5. However, selection could have skewed sequence evolution in introns and exons. In addition, some of the X-Y gene pairs studied lie within chromosomal regions with substantially divergent nucleotide sequences. Here we directly compare human X and Y sequences within a large region with no known genes. Here the two chromosomes are 99% identical, and X-Y divergence began only three or four million years ago, during hominid evolution. In apes, homologous sequences exist only on the X chromosome. We sequenced and compared 38.6 kb of this region from human X, human Y, chimpanzee X and gorilla X chromosomes. We calculated alpha(m) to be 1.7 (95% confidence interval 1.15-2.87), significantly lower than previous estimates in primates. We infer that, in humans and their immediate ancestors, male and female mutation rates were far more similar than previously supposed.     

The DNA sequence and analysis of human chromosome 14

Chromosome 14 is one of five acrocentric chromosomes in the human genome. These chromosomes are characterized by a heterochromatic short arm that contains essentially ribosomal RNA genes, and a euchromatic long arm in which most, if not all, of the protein-coding genes are located. The finished sequence of human chromosome 14 comprises 87,410,661 base pairs, representing 100% of its euchromatic portion, in a single continuous segment covering the entire long arm with no gaps. Two loci of crucial importance for the immune system, as well as more than 60 disease genes, have been localized so far on chromosome 14. We identified 1,050 genes and gene fragments, and 393 pseudogenes. On the basis of comparisons with other vertebrate genomes, we estimate that more than 96% of the chromosome 14 genes have been annotated. From an analysis of the CpG island occurrences, we estimate that 70% of these annotated genes are complete at their 5' end.     

Generation and annotation of the DNA sequences of human chromosomes 2 and 4

Human chromosome 2 is unique to the human lineage in being the product of a head-to-head fusion of two intermediate-sized ancestral chromosomes. Chromosome 4 has received attention primarily related to the search for the Huntington's disease gene, but also for genes associated with Wolf-Hirschhorn syndrome, polycystic kidney disease and a form of muscular dystrophy. Here we present approximately 237 million base pairs of sequence for chromosome 2, and 186 million base pairs for chromosome 4, representing more than 99.6% of their euchromatic sequences. Our initial analyses have identified 1,346 protein-coding genes and 1,239 pseudogenes on chromosome 2, and 796 protein-coding genes and 778 pseudogenes on chromosome 4. Extensive analyses confirm the underlying construction of the sequence, and expand our understanding of the structure and evolution of mammalian chromosomes, including gene deserts, segmental duplications and highly variant regions.     

Comparison between phylogeny of introns and exons in primates

Introns and exons of 7 genes ( epsilon globin, gamma-1 globin, gamma-2 globin, delta globin, beta globin, Immunoglobulin and prepro-insulin) in primates have been separated out and used to infer phylogeny respectively. For each gene, results based on these two parts have been compared and showed that: ( i ) the topology of introns is almost consistent with that of exons in each gene, while the branch length of them varies, because of the different mutation rate; ( ii ) there is evidence that the substitution rate of exons would decrease in hominoids, but that of introns would not; (iii) divergence time of orangutan deduced from different genes based on exons is various, while that based on introns is much similar, and consistent with fossil records; (iv) there is a relationship between the G + C content and the substitution rate. When the substitution rate of introns is higher than exons in a gene, the G + C content of introns is less. The above results suggest that introns could provide useful evolutionary information among closely related species.     

Comparison between phylogeny of introns and exons in primate

Introns and exons of 7 genes (epsilon globin, gamma-1 globin, gamma-2 globin, delta globin, beta globin, Immunoglobulin andprepro-insulin) in primates have been separated out and used to infer phylogeny respectively. For each gene, results based on these two parts have been compared and showed that: (i) the topology of introns is almost consistent with that of exons in each gene, while the branch length of them varies, because of the dierent mutation rate; (ii) there is evidence that the substitution rate of exons would decrease inhominoids, but that of introns would not; (iii) divergence time of orangutan deduced from different genes based on exons is various, while that based on introns is much similar, and consistent with fossil records; (iv) there is a relationship between the G + C content and the substitution rate. When the substitution rate of introns is higher than exons in a gene, the G + C content of introns is less. The above results suggest that introns could provide useful evolutionary information among closety related species.     

Dispersed human immunoglobulin kappa light-chain genes

The gene segments encoding the constant and variable regions of human immunoglobulin light chains of the kappa type (C kappa, V kappa) have been localized to chromosome 2. The distance between the C kappa and V kappa genes and the number of germline V kappa genes are unknown. As part of our work on the human V kappa locus, we have now mapped two solitary V kappa gene and a cluster of three V kappa genes to chromosomes 1, 15 and 22, respectively. The three genes that have been sequenced are nonprocessed pseudogenes, and the same may be true for the other two genes. This is the first time that V-gene segments have been found outside the C-gene-containing chromosomes. Our finding is relevant to current estimates of the size of the V kappa-gene repertoire. Furthermore, the dispersed gene regions have some unusual characteristics which may help to clarify the mechanism of dispersion.     

Aberrant rearrangement of the kappa light-chain locus involving the heavy-chain locus and chromosome 15 in a mouse plasmacytoma

The creation of a functional antibody gene requires the precise recombination of gene segments initially separated on the chromosome. Frequently errors occur in the process, resulting in the formation of a non-functional gene. The non-functional genes can be generated by incomplete rearrangements, frameshifts, or the use of pseudo V or J joining segments. It is likely that these aberrant rearrangements arise by the same mechanism as is used in generating functional genes, a process which we have suggested may involve unequal sister chromatid exchange. Aberrant rearrangements of immunoglobulin genes occur in normal lymphocytes and play a major part in allelic exclusion. However, it has recently been suggested that aberrant rearrangements involving immunoglobulin and non-immunoglobulin genes may be involved in tumorigenesis. This suggestion has been stimulated by the frequent occurrence of translocations involving chromosomes known to carry immunoglobulin genes in B-cell malignancies. The rearrangement of non-immunoglobulin DNA to the heavy-chain locus has recently been reported. Some aberrant rearrangements of the kappa locus appear to be due to rearrangements to sites that do not include the conventional sequence for V gene segment joining. Here we describe an aberrant kappa rearrangement that has led to the joining of DNA from chromosomes 15, 6 and 12, and so appears to be the result of chromosomal translocations or transpositions. As 15/6 or 15/12 translocations have frequently been found in mouse plasmacytomas (as have analogous translocations in human lymphocyte tumours) this aberrant kappa rearrangement may be unique to the plasmacytoma from which it was isolated.