Sandoval-Motta Santiago, Aldana Maximino, Martínez-Romero Esperanza, Frank Alejandro
Centro de Ciencias de la Complejidad, Universidad Nacional Autónoma de MéxicoMexico City, Mexico.
Instituto de Ciencias Físicas, Universidad Nacional Autónoma de MéxicoMorelos, Mexico.
Front Genet. 2017 Jun 13;8:80. doi: 10.3389/fgene.2017.00080. eCollection 2017.
The "missing heritability" problem states that genetic variants in Genome-Wide Association Studies (GWAS) cannot completely explain the heritability of complex traits. Traditionally, the heritability of a phenotype is measured through familial studies using twins, siblings and other close relatives, making assumptions on the genetic similarities between them. When this heritability is compared to the one obtained through GWAS for the same traits, a substantial gap between both measurements arise with genome wide studies reporting significantly smaller values. Several mechanisms for this "missing heritability" have been proposed, such as epigenetics, epistasis, and sequencing depth. However, none of them are able to fully account for this gap in heritability. In this paper we provide evidence that suggests that in order for the phenotypic heritability of human traits to be broadly understood and accounted for, the compositional and functional diversity of the human microbiome must be taken into account. This hypothesis is based on several observations: (A) The composition of the human microbiome is associated with many important traits, including obesity, cancer, and neurological disorders. (B) Our microbiome encodes a second genome with nearly a 100 times more genes than the human genome, and this second genome may act as a rich source of genetic variation and phenotypic plasticity. (C) Human genotypes interact with the composition and structure of our microbiome, but cannot by themselves explain microbial variation. (D) Microbial genetic composition can be strongly influenced by the host's behavior, its environment or by vertical and horizontal transmissions from other hosts. Therefore, genetic similarities assumed in familial studies may cause overestimations of heritability values. We also propose a method that allows the compositional and functional diversity of our microbiome to be incorporated to genome wide association studies.
“缺失遗传力”问题指出，全基因组关联研究（GWAS）中的基因变异无法完全解释复杂性状的遗传力。传统上，表型的遗传力是通过对双胞胎、兄弟姐妹和其他近亲进行家族研究来衡量的，并假设他们之间存在遗传相似性。当将这种遗传力与通过GWAS针对相同性状获得的遗传力进行比较时，两种测量结果之间会出现很大差距，全基因组研究报告的值明显较小。针对这种“缺失遗传力”，已经提出了几种机制，如表观遗传学、上位性和测序深度。然而，它们都无法完全解释遗传力上的这一差距。在本文中，我们提供的证据表明，为了全面理解和解释人类性状的表型遗传力，必须考虑人类微生物组的组成和功能多样性。这一假设基于以下几点观察：（A）人类微生物组的组成与许多重要性状相关，包括肥胖、癌症和神经系统疾病。（B）我们的微生物组编码了一个第二个基因组，其基因数量几乎是人类基因组的100倍，这个第二个基因组可能是丰富的遗传变异和表型可塑性来源。（C）人类基因型与我们微生物组的组成和结构相互作用，但自身无法解释微生物变异。（D）微生物遗传组成会受到宿主行为、其环境或其他宿主的垂直和水平传播的强烈影响。因此，家族研究中假设的遗传相似性可能会导致遗传力值的高估。我们还提出了一种方法，可将我们微生物组的组成和功能多样性纳入全基因组关联研究。
