生物谷:精子在精巢的激烈竞争可能是造成婴儿头骨发育异常以及连指(趾)的原因。一项新的研究指出,这种遗传信号似乎能通过提高分裂速度给一些先驱精子造成某种优势。
每七万名儿童中就有一个被阿佩尔综合征所折磨,他们在出生时头部、手、脚的骨骼就处于软化状态。这种病的影响范围尽管看起来不算高,却仍是平均突变率的100-1000倍。这种缺陷发生在染色体10上单独一个基因的某一点,与父亲的年龄有关。研究人员首次得出推论认为这一位置可能对基因误差敏感,是一个突变“热点”。最近不少研究指出这种突变可能会在自然选择中给予源生细胞(精子先驱)某种优势。
南加州大学(USC)的计算生物学家Peter Calabrese开发出演绎在各种情况下突变是如何产生和发展的数学模型。假如热点模型成立,突变细胞在精巢中应该是平均分布的;如果选择模型成立,突变体则应该是成簇存在的,中间几乎没有变异细胞。为了对情况进行测试,USC的分子遗传学家Norman Arnheim及其同事通过解剖精巢发现,50多岁和60多岁的男人携带和传递突变的概率是30岁以下男人的10倍。研究小组用Calabrese的模型比较了突变胚原细胞的分布,他们发现突变体是聚集成簇的,就像选择模型一样。这项研究结果发表在本周的《PLoS生物学》在线版上,认为是这种突变使这些细胞更容易自我复制或者在非突变胚原细胞中存活。这些突变细胞的积累可以解释为什么大龄父亲的小孩有更高风险患阿佩尔综合征。
Arnheim希望这项研究结果能改变遗传学家对人类基因突变的一些看法。他说,你可能会发生一种突变导致一种严重的不利条件,但是这种突变却有着选择性优势。
威斯康星大学的遗传学家James Crow说,这些发现首次为我们解答了世纪之谜——与年老父亲有关的遗传条件——如阿佩尔综合征以及软骨发育不全侏儒症。把这个弄清很有必要,这是一个很好的观点,不但新而且是惊人的,也是非常有趣的。
塔头并指症(Apert syndrome)会使人的头骨、手指及脚趾发育畸形,大约每15万新生儿中就有一人患有此症,并且绝大多数患者都是由于基因突变造成的。美国科学家通过对睾丸细胞的深入研究,揭示了这一病症的内在机制。相关论文发表在最新一期的《PLoS生物学》上。
科学家研究发现,导致塔头并指症的突变(称作C755G),即与骨生长有关的基因的DNA序列的微小的变化,在精子中出现的次数比预想的要高出100-1000多倍。这令科学家们迷惑不解,因为,如果说突变是随机的,那么在精子中出现的频率为何如此之高?
遗传学家曾经提出了两种理论来解释这种现象:一种称作突变热点(mutation hotspot)模型,认为当DNA复制时,C755G位点非常容易出错;另一种称作自私精子(selfish sperm)模型,认为C755G会使细胞获得生长优势,所以一旦精原细胞(sperm-making cell)偶然发生突变,突变细胞就会大量生长起来。
在最新的研究中,美国南加州大学的Norman Arnheim和同事将人类睾丸切成200余片,通过分析这些片断的DNA,建立三维图像,研究人员查明了带有C755G突变的精原细胞的具体位点。
结果发现,C755G细胞丛生在一起。计算机模拟实验证实,如果按照突变热点模型,这种丛生现象是不会发生的。而从另外一面来说,这一结果与自私精子模型则非常吻合,即C755G增强了细胞的复制能力,所以突变的细胞会大量生长起来,形成丛生的现象。
英国牛津大学的Andrew Wilkie认为,此次研究为自私精子模型提供了新的佐证。他同时表示,这种突变与癌细胞不受控制的增长具有相似之处,并且最近已在子宫内膜瘤中观测到C755G突变,但是它在其中的具体作用还有待深入研究。(科学网 梅进/编译)
原始出处:
PLoS Biology
doi:10.1371/journal.pbio.0050224.g001
Received: February 23, 2007; Accepted: June 19, 2007; Published: August 28, 2007
The Molecular Anatomy of Spontaneous Germline Mutations in Human Testes
Jian Qin1¤, Peter Calabrese1, Irene Tiemann-Boege1, Deepali Narendra Shinde1, Song-Ro Yoon1, David Gelfand2, Keith Bauer2, Norman Arnheim1*
1 Molecular and Computational Biology Program, University of Southern California, Los Angeles, California, United States of America, 2 Program in Core Research, Roche Molecular Systems, Alameda, California, United States of America
The frequency of the most common sporadic Apert syndrome mutation (C755G) in the human fibroblast growth factor receptor 2 gene (FGFR2) is 100–1,000 times higher than expected from average nucleotide substitution rates based on evolutionary studies and the incidence of human genetic diseases. To determine if this increased frequency was due to the nucleotide site having the properties of a mutation hot spot, or some other explanation, we developed a new experimental approach. We examined the spatial distribution of the frequency of the C755G mutation in the germline by dividing four testes from two normal individuals each into several hundred pieces, and, using a highly sensitive PCR assay, we measured the mutation frequency of each piece. We discovered that each testis was characterized by rare foci with mutation frequencies 103 to >104 times higher than the rest of the testis regions. Using a model based on what is known about human germline development forced us to reject (p < 10−6) the idea that the C755G mutation arises more frequently because this nucleotide simply has a higher than average mutation rate (hot spot model). This is true regardless of whether mutation is dependent or independent of cell division. An alternate model was examined where positive selection acts on adult self-renewing Ap spermatogonial cells (SrAp) carrying this mutation such that, instead of only replacing themselves, they occasionally produce two SrAp cells. This model could not be rejected given our observed data. Unlike the disease site, similar analysis of C-to-G mutations at a control nucleotide site in one testis pair failed to find any foci with high mutation frequencies. The rejection of the hot spot model and lack of rejection of a selection model for the C755G mutation, along with other data, provides strong support for the proposal that positive selection in the testis can act to increase the frequency of premeiotic germ cells carrying a mutation deleterious to an offspring, thereby unfavorably altering the mutational load in humans. Studying the anatomical distribution of germline mutations can provide new insights into genetic disease and evolutionary change.
Figure 1.Testes Dissection Strategy
Testes 374–1, 374–2, and 854–2. After slicing each testis in half, perpendicular to the epididymal axis, the two halves were each divided into three slices along the same axis for a total six slices. Each slice is then cut into 32 pieces and each piece is numbered (see inset for slice 3) to provide a binomial classification system (e.g., slice 3 piece 17). Note that there is some variation in slice and piece size because of the shape of the testis. This is reflected in the number of genomes per piece (see Table S1).
全文链接:
http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0050224