母親的線粒體DNA，會影響后代的身高、壽命和疾病風險

Mitochondria—the 'batteries' that power our cells—play an unexpected role in common diseases such as type 2 diabetes and multiple sclerosis, concludes a study of over 350,000 people conducted by the University of Cambridge.

劍橋大學對35萬人進行的一項研究表明，線粒體——為我們的細胞提供能量的“電池”——在常見疾病(如2型糖尿病和多發(fā)性硬化癥)中發(fā)揮著意想不到的作用。

The study, published today in Nature Genetics, found that genetic variants in the DNA of mitochondria could increase the risk of developing these conditions, as well influencing characteristics such as height and lifespan.

這項研究發(fā)表在今天的《自然·遺傳學》(Nature Genetics)雜志上，研究發(fā)現(xiàn)：線粒體DNA的基因變異，可能會增加患這些疾病的風險，并影響身高和壽命等特征。

There was also evidence that some changes in mitochondrial DNA were more common in people with Scottish, Welsh or Northumbrian genetic ancestry, implying that mitochondrial DNA and nuclear DNA (which accounts for 99.9% of our genetic make-up) interact with each other.

也有證據(jù)表明，線粒體DNA的一些變化在蘇格蘭、威爾士或諾森伯蘭遺傳祖先中更常見，這意味著線粒體DNA和核DNA(占我們基因組成的99.9%)相互作用。

Credit: Pixabay/CC0 Public Domain

Almost all of the DNA that makes up the human genome—the body's 'blueprint' - is contained within the nuclei of our cells. Among other functions, nuclear DNA codes for the characteristics that make us individual as well as for the proteins that do most of the work in our bodies.

幾乎所有構(gòu)成人類基因組的DNA——人體的“藍圖”——都包含在細胞核中。在其他功能中，核DNA編碼使我們成為個體的特征，以及完成我們身體大部分工作的蛋白質(zhì)。

Our cells also contain mitochondria, often referred to as 'batteries', which provide the energy for our cells to function. They do this by converting the food that we eat into ATP, a molecule capable of releasing energy very quickly. Each of these mitochondria is coded for by a tiny amount of 'mitochondrial DNA'. Mitochondrial DNA makes up only 0.1% of the overall human genome and is passed down exclusively from mother to child.

我們的細胞也含有線粒體，它為我們的細胞提供運行所需的能量。它們通過將我們吃的食物轉(zhuǎn)化為ATP來達到這一目的，ATP是一種能夠快速釋放能量的分子。每一個線粒體都由少量的“線粒體DNA”編碼。線粒體DNA只占人類基因總數(shù)的0.1%，而且只從母親遺傳給孩子。

While errors in mitochondrial DNA can lead to so-called mitochondrial diseases, which can be severely disabling, until now there had been little evidence that these variants can influence more common diseases. Several small-scale studies have hinted at this possibility, but scientists have been unable to replicate their findings.

雖然線粒體DNA的錯誤，可能會導致所謂的線粒體疾病，從而導致嚴重的殘疾，但到目前為止，幾乎沒有證據(jù)表明這些變異會影響更常見的疾病。一些小規(guī)模的研究，已經(jīng)暗示了這種可能性，但科學家們一直無法復制他們的發(fā)現(xiàn)。

Now, a team at the University of Cambridge has developed a new technique to study mitochondrial DNA and its relation to human diseases and characteristics in samples taken from 358,000 volunteers as part of UK Biobank, a large-scale biomedical database and research resource.

現(xiàn)在，劍橋大學(University of Cambridge)的一個研究小組開發(fā)了一種新技術(shù)，研究取自358000名志愿者樣本的線粒體DNA及其與人類疾病和特征的關(guān)系。這些樣本是英國生物樣本庫(UK Biobank)的一部分。

Dr. Joanna Howson, who carried out the work while at the Department of Public Health and Primary Care at the University of Cambridge, said: "Using this new method, we've been able to look for associations between the numerous features that have been recorded for participants of UK Biobank and see whether any correlate with mitochondrial DNA.

劍橋大學公共衛(wèi)生和初級護理學系的喬安娜·豪森(Joanna Howson)博士表示：“使用這種新方法，我們已經(jīng)能夠?qū)ふ谊P(guān)聯(lián)的眾多特性，記錄了參與者之間的英國生物庫，看是否與線粒體DNA相關(guān)聯(lián)。”

"Aside from mitochondrial diseases, we don't generally associate mitochondrial DNA variants with common diseases. But what we've shown is that mitochondrial DNA—which we inherit from our mother—influences the risk of some diseases such as type 2 diabetes and MS as well as a number of common characteristics."

“除了線粒體疾病，我們通常不會將線粒體DNA變異與常見疾病聯(lián)系起來。但我們已經(jīng)證明，人類從母親那里繼承的線粒體DNA會影響一些疾病的風險，如2型糖尿病和多發(fā)性硬化，以及一些共同特征。”

Among those factors found to be influenced by mitochondrial DNA are: type 2 diabetes, multiple sclerosis, liver and kidney function, blood count parameters, life span and height. While some of the effects are seen more extremely in patients with rare inherited mitochondrial diseases—for example, patients with severe disease are often shorter than average—the effect in healthy individuals tends to be much subtler, likely accounting for just a few millimetres' height difference, for example.

在這些被發(fā)現(xiàn)受線粒體DNA影響的因素中有：2型糖尿病、多發(fā)性硬化癥、肝腎功能、血細胞計數(shù)參數(shù)、壽命和身高。雖然有些影響在患有罕見遺傳性線粒體疾病的患者身上表現(xiàn)得更為明顯——例如，患有嚴重疾病的患者往往比平均身高要短——但在健康個體身上的影響往往要微妙得多，例如，可能只有幾毫米的身高差異。

There are several possible explanations for how mitochondrial DNA exerts its influence. One is that changes to mitochondrial DNA lead to subtle differences in our ability to produce energy. However, it is likely to be more complicated, affecting complex biological pathways inside our bodies—the signals that allow our cells to operate in a coordinated fashion.

線粒體疾病目前沒有治愈方法。對于線粒體DNA如何發(fā)揮其影響，有幾種可能的解釋。一是線粒體DNA的改變，導致我們產(chǎn)生能量的能力發(fā)生細微的變化。然而，它可能更復雜，影響我們體內(nèi)復雜的生物途徑——讓我們的細胞以協(xié)調(diào)的方式運作的信號。

Professor Patrick Chinnery from the MRC Mitochondrial Biology Unit at Cambridge said: "If you want a complete picture of common diseases, then clearly you're going to need to factor in the influence of mitochondrial DNA. The ultimate aim of studies of our DNA is to understand the mechanisms that underlie these diseases and find new ways to treat them. Our work could help identify potential new drug targets."

來自英國醫(yī)學研究委員會線粒體生物學小組的Patrick Chinnery教授表示：“如果你想了解常見疾病的完整情況，那么顯然你需要考慮線粒體DNA的影響。對我們DNA研究的最終目的是了解這些疾病背后的機制，并找到治療它們的新方法。我們的工作可以幫助確定潛在的新藥物靶點。”

Unlike nuclear DNA, which is passed down from both the mother and the father, mitochondria DNA is inherited exclusively from the mother. This suggests that the two systems are inherited independently and hence there should be no association between an individual's nuclear and mitochondrial DNA—however, this was not what the team found.

研究人員表明，特定的核遺傳背景優(yōu)先與特定的線粒體遺傳背景相關(guān)，尤其是在蘇格蘭、威爾士和諾森比亞。這表明，我們的核基因組和線粒體基因組已經(jīng)進化，并將繼續(xù)進化，彼此相互作用。

The researchers showed that certain nuclear genetic backgrounds are associated preferentially with certain mitochondrial genetic backgrounds, particularly in Scotland, Wales and Northumbria. This suggests that our nuclear and mitochondrial genomes have evolved—and continue to evolve—side-by-side and interact with each other.

其中一個原因可能是兼容性的需要。ATP是由線粒體內(nèi)一組稱為呼吸鏈的蛋白質(zhì)產(chǎn)生的。呼吸鏈有100多種成分，其中13種是由線粒體DNA編碼的;其余的由核DNA編碼。盡管呼吸鏈中的蛋白質(zhì)是由兩個不同的基因組產(chǎn)生的，但這些蛋白質(zhì)需要像拼圖一樣在物理上相互連鎖。

One reason that may explain this is the need for compatibility. ATP is produced by a group of proteins inside the mitochondria, called the respiratory chain. There are over 100 components of the respiratory chain, 13 of which are coded for by mitochondrial DNA; the remainder are coded for by nuclear DNA. Even though proteins in the respiratory chain are being produced by two different genomes, the proteins need to physically interlock like pieces of a jigsaw.

如果孩子遺傳的線粒體DNA與父親遺傳的核DNA不相容，拼圖就不能正確地組合在一起，從而影響呼吸鏈，進而影響能量生產(chǎn)。這可能會微妙地影響一個人的健康或生理，從進化的角度來看，隨著時間的推移，這可能是不利的。相反，匹配會被進化所鼓勵，因此變得更加普遍。

If the mitochondrial DNA inherited by a child was not compatible with the nuclear DNA inherited from the father, the jigsaw would not fit together properly, thereby affecting the respiratory chain and, consequently, energy production. This might subtly influence an individual's health or physiology, which over time could be disadvantageous from an evolutionary perspective. Conversely, matches would be encouraged by evolution and therefore become more common.

此前還有研究表明，DNA測序表明，年齡越大的母親，自身細胞的線粒體DNA突變越多。而高齡母親生育的孩子，也更易患線粒體疾病。

This could have implications for the success of mitochondrial transfer therapy—a new technique that enables scientists to replace a mother's defective mitochondria with those from a donor, thereby preventing her child from having a potentially life-threatening mitochondrial disease.

這可能意味著線粒體轉(zhuǎn)移治療的成功——一項新技術(shù)使科學家能夠用捐贈者的線粒體替換母親有缺陷的線粒體，從而防止她的孩子患有潛在的危及生命的線粒體引發(fā)的疾病。