这项研究是由皇冠hga025大学洛杉矶分校的健康博士领导的. 列昂尼德•Kruglyak.
几千年来，酵母菌物种 酿酒酵母 has been one of humanity’s most useful microbial workhorses — transforming flour into bread, 葡萄制成葡萄酒，谷物制成啤酒, 在其他任务中. S. 酵母 also serves as a handy tool for biologists: a single-celled fungus, 很容易在实验室培养, whose metabolic processes can serve as a model for those of more complex creatures. 根据a 新的研究 皇冠hga025大学洛杉矶分校的研究人员, this organism’s dietary habits may shed light on a genetic disorder that makes dairy products crippling or deadly to some people, 并可能导致新的治疗方法.
S. 酵母 葡萄糖是一种所有植物都能产生的糖. Although the species can also consume galactose — a breakdown product of lactose, the main sugar in milk — most 菌株 take several hours to activate the genetic pathway that enables them to do so. 近年来, 然而, 科学家们已经发现一些菌株, 通常存在于奶酪和酸奶等食物中, 能更快地开始处理半乳糖吗, 并在上面茁壮成长, 比他们的传统对手. Little is known about the genetic differences that allow dairy-loving 菌株 to metabolize this particular sugar so well.
Unraveling the mysteries of such complex heritable traits is the mission of 列昂尼德•Kruglyak, 博士学位, Diller-von Furstenberg Family Endowed Chair in Human 遗传学, Distinguished Professor of Human 遗传学 and Biological Chemistry at the David Geffen 医学院 at UCLA and a Howard Hughes Medical Institute investigator. “我的实验室,他解释道, “uses model organisms and computational analyses to understand how changes at the level of DNA are shaped by molecular and evolutionary forces, and how these changes lead to the observable differences among members of a species.”
在一个 之前的研究, Dr. Kruglyak and his team looked for potential associations between DNA variants and inherited traits in more than 10,000个培养物由16个菌株杂交而成 S. 酵母. Among the most remarkable results were those involving a soil strain dubbed CBS2888. 当这个菌株与其他菌株杂交时, there were striking interactions between three loci (stretches of DNA) known to contain genes crucial to the galactose pathway: some combinations of variants at these loci correlated with much slower than normal growth on galactose.
在发表在杂志上的新论文中 科学, 博士领导的研究. Kruglyak’s graduate student James Boocock pushed these findings further. 第一个, the team sequenced CBS2888’s DNA and found that its galactose-related genes were radically different from those of conventional S. 酵母. “They could have come from another species altogether,” Boocock says. “这就像比较人类和老鼠的基因一样.”
下一个, the researchers used the gene-editing technology CRISPR to engineer 菌株 with every possible combination of the “reference” (conventional) and “alternative” (CBS2888) galactose genes. The strain that grew best on galactose was the one whose genes in all three loci came from CBS2888 — indicating that this soil yeast had somehow evolved to specialize in a sugar typically associated with lactating mammals. The runner-up was the strain whose galactose genes all came from conventional S. 酵母. To the researchers’ surprise, 菌株 with the 混合-and-matched genes from both sources grew poorly.
Puzzled, the team combed through global collections of sequenced S. 酵母 菌株, looking for reference and alternative galactose gene versions — or alleles — outside the lab. 在1,276株, they found two common combinations: only reference alleles (1,213株)，只有选择性等位基因(49株)。. The alternative alleles showed up in dairy products ranging from French Camembert to Chinese fermented yak milk. 然而，完全缺失的是带有 混合 alleles, like those the UCLA team had created with CRISPR. If such 菌株 ever existed in nature, they had apparently died out.
基于这些证据, the researchers theorized that evolution had maintained the different versions of the galactose pathway through “balancing selection” — a process that preserves alternative alleles when each version provides a species with a survival advantage. The best-known example of this phenomenon is the sickle-cell gene, which generates misshapen red blood cells: While individuals who carry two copies of the gene often die young, 只有一个副本的人通常不会出现任何症状, 并且免受疟疾的侵害.
One remaining question was how long the alternative galactose pathway has existed in S. 酵母. When the team analyzed the reference and alternative alleles, 他们发现分裂发生在3点左右.20亿代以前，也就是1000万到2000万年前. “这早于最近的共同祖先 酿酒 布科克指出. “Ancestral yeasts may have used this pathway to feed on plants with a high galactose content. Or some may have evolved in a ‘cheese-like’ environment created by mammals suckling their pups.”
那么这一切与人类健康有什么关系呢? The incompatible allele combinations the team identified may provide a model for a rare metabolic disease: classical galactosemia. People with this inherited disorder are unable to metabolize galactose; breast milk or dairy-based formula can kill them in infancy. 即使病人不吃乳制品, 人体自己制造少量的半乳糖, 常常导致智力缺陷, 运动障碍, 白内障和其他疾病.
半乳糖血症是由GALT基因突变引起的, 这种基因相当于人类的酵母半乳糖基因. Kruglyak的团队正在进行研究. “This disease is reminiscent of the ‘sickness’ we see in combination 菌株 grown in the lab,他说. “我们的研究可以深入了解其机制, and hopefully suggest avenues for developing treatments.”
Kenneth Miller是这篇文章的作者.
