生物谷：精子在精巢的激烈競爭可能是造成嬰兒頭骨發(fā)育異常以及連指（趾）的原因,。一項新的研究指出,，這種遺傳信號似乎能通過提高分裂速度給一些先驅(qū)精子造成某種優(yōu)勢。
每七萬名兒童中就有一個被阿佩爾綜合征所折磨,，他們在出生時頭部,、手、腳的骨骼就處于軟化狀態(tài),。這種病的影響范圍盡管看起來不算高,，卻仍是平均突變率的100－1000倍,。這種缺陷發(fā)生在染色體10上單獨一個基因的某一點，與父親的年齡有關(guān),。研究人員首次得出推論認為這一位置可能對基因誤差敏感,，是一個突變“熱點”。最近不少研究指出這種突變可能會在自然選擇中給予源生細胞（精子先驅(qū)）某種優(yōu)勢,。
南加州大學（USC）的計算生物學家Peter Calabrese開發(fā)出演繹在各種情況下突變是如何產(chǎn)生和發(fā)展的數(shù)學模型,。假如熱點模型成立，突變細胞在精巢中應該是平均分布的,；如果選擇模型成立,，突變體則應該是成簇存在的，中間幾乎沒有變異細胞,。為了對情況進行測試,，USC的分子遺傳學家Norman Arnheim及其同事通過解剖精巢發(fā)現(xiàn),，50多歲和60多歲的男人攜帶和傳遞突變的概率是30歲以下男人的10倍,。研究小組用Calabrese的模型比較了突變胚原細胞的分布，他們發(fā)現(xiàn)突變體是聚集成簇的,，就像選擇模型一樣,。這項研究結(jié)果發(fā)表在本周的《PLoS生物學》在線版上，認為是這種突變使這些細胞更容易自我復制或者在非突變胚原細胞中存活,。這些突變細胞的積累可以解釋為什么大齡父親的小孩有更高風險患阿佩爾綜合征,。
Arnheim希望這項研究結(jié)果能改變遺傳學家對人類基因突變的一些看法。他說,，你可能會發(fā)生一種突變導致一種嚴重的不利條件,，但是這種突變卻有著選擇性優(yōu)勢。
威斯康星大學的遺傳學家James Crow說,，這些發(fā)現(xiàn)首次為我們解答了世紀之謎——與年老父親有關(guān)的遺傳條件——如阿佩爾綜合征以及軟骨發(fā)育不全侏儒癥,。把這個弄清很有必要，這是一個很好的觀點,，不但新而且是驚人的,，也是非常有趣的。
塔頭并指癥（Apert syndrome）會使人的頭骨,、手指及腳趾發(fā)育畸形,，大約每15萬新生兒中就有一人患有此癥，并且絕大多數(shù)患者都是由于基因突變造成的,。美國科學家通過對睪丸細胞的深入研究,，揭示了這一病癥的內(nèi)在機制。相關(guān)論文發(fā)表在最新一期的《PLoS生物學》上,。
科學家研究發(fā)現(xiàn),，導致塔頭并指癥的突變（稱作C755G）,，即與骨生長有關(guān)的基因的DNA序列的微小的變化，在精子中出現(xiàn)的次數(shù)比預想的要高出100－1000多倍,。這令科學家們迷惑不解,，因為，如果說突變是隨機的,，那么在精子中出現(xiàn)的頻率為何如此之高,？
遺傳學家曾經(jīng)提出了兩種理論來解釋這種現(xiàn)象：一種稱作突變熱點（mutation hotspot）模型，認為當DNA復制時,，C755G位點非常容易出錯,；另一種稱作自私精子（selfish sperm）模型，認為C755G會使細胞獲得生長優(yōu)勢,，所以一旦精原細胞（sperm-making cell）偶然發(fā)生突變,，突變細胞就會大量生長起來。
在最新的研究中,，美國南加州大學的Norman Arnheim和同事將人類睪丸切成200余片,，通過分析這些片斷的DNA，建立三維圖像,，研究人員查明了帶有C755G突變的精原細胞的具體位點,。
結(jié)果發(fā)現(xiàn)，C755G細胞叢生在一起,。計算機模擬實驗證實,，如果按照突變熱點模型，這種叢生現(xiàn)象是不會發(fā)生的,。而從另外一面來說,，這一結(jié)果與自私精子模型則非常吻合，即C755G增強了細胞的復制能力,，所以突變的細胞會大量生長起來,，形成叢生的現(xiàn)象。
英國牛津大學的Andrew Wilkie認為,，此次研究為自私精子模型提供了新的佐證,。他同時表示，這種突變與癌細胞不受控制的增長具有相似之處,，并且最近已在子宮內(nèi)膜瘤中觀測到C755G突變,，但是它在其中的具體作用還有待深入研究。（科學網(wǎng) 梅進/編譯）
原始出處:
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).
全文鏈接：
http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0050224
