Tibayrenc Michel
Institut pour la Recherche et Développement (IRD) Representative Office, French Embassy, 29 Thanon Sathorn Tai, Bangkok 10120, Thailand.
Adv Parasitol. 2007;64:377-422. doi: 10.1016/S0065-308X(06)64004-9.
This paper aims to review human genetic studies that are generally poorly known by parasitologists and scientists working on other pathogenic agents. The key proposals of this paper are as follows: (i) human susceptibility to transmissible diseases may often have a complex, multigenic background; (ii) recent discoveries indicate that major genomic rearrangements may be involved, possibly more so than DNA sequence; (iii) it is crucial to have a general population genetics framework of the human species based on neutral/historical markers to analyse reliably genetic susceptibility to infectious diseases; and (iv) the population level is a key factor. Ethnic diversity, a highly adaptive genetically driven phenotypic diversity, is possibly a valuable source for exploring human genetic susceptibility to transmissible diseases, since different populations have been exposed to drastically different geographic/climatic environments and different pathogens and vectors for tens of thousands of years. Studies dealing with human genetic susceptibility to transmissible diseases have mostly been based on the hypothesis that this factor is driven by only one or a few genes, and considered the individual more than the population level. Two different approaches have been developed for identifying the genes involved: (i) candidate genes and (ii) blind association studies (linkage analysis), screening the genome with a large number of high-resolution markers. Some loci involved in susceptibility to leishmaniosis, malaria and schistosomosis, for example, have already been identified. South American trypanosomosis (Chagas disease) is reviewed in detail to show the methodological problems of this classical approach. Current knowledge on the general impact of transmissible diseases on human genetic diversity, mainly HLA polymorphism, and the hopes raised by recent major international programmes such as the Human Genome Project (HGP), Human Genome Diversity Project (HGDP), International Human Haplotype Map Project (Hap Map) and extended databases, networks and networks of networks will also be reviewed.
本文旨在回顾人类遗传学研究，而寄生虫学家以及研究其他病原体的科学家们通常对这些研究知之甚少。本文的主要提议如下：（i）人类对传染性疾病的易感性可能往往具有复杂的多基因背景；（ii）最近的发现表明，可能涉及主要的基因组重排，其程度可能超过DNA序列；（iii）基于中性/历史标记构建人类物种的一般群体遗传学框架，对于可靠地分析对传染病的遗传易感性至关重要；（iv）群体水平是一个关键因素。种族多样性是一种由遗传驱动的高度适应性表型多样性，可能是探索人类对传染性疾病遗传易感性的宝贵资源，因为不同群体在数万年的时间里接触了截然不同的地理/气候环境以及不同的病原体和病媒。关于人类对传染性疾病遗传易感性的研究大多基于这样一种假设，即该因素仅由一个或几个基因驱动，并且更多地考虑个体而非群体水平。已经开发出两种不同的方法来鉴定相关基因：（i）候选基因法和（ii）盲法关联研究（连锁分析），即用大量高分辨率标记筛选基因组。例如，已经确定了一些与利什曼病、疟疾和血吸虫病易感性相关的基因座。本文详细回顾了南美洲锥虫病（恰加斯病），以展示这种经典方法存在的方法学问题。还将回顾关于传染性疾病对人类遗传多样性（主要是HLA多态性）的总体影响的现有知识，以及诸如人类基因组计划（HGP）、人类基因组多样性计划（HGDP）、国际人类单倍型图谱计划（Hap Map）等近期重大国际项目以及扩展数据库、网络和网络之网络所带来的希望。
