Facultad de Ciencias, Universidad de Los Andes, Bogotá, Colombia.
Applied Bioinformatics Laboratory, Atlanta, Georgia, United States of America.
PLoS One. 2024 Nov 18;19(11):e0313777. doi: 10.1371/journal.pone.0313777. eCollection 2024.
Autosomal recessive conditions are often associated with homozygous mutations showing common ancestral origins and are frequently linked to consanguinity. However, an increasing number of compound heterozygotes are found in diverse, admixed populations. Oculocutaneous albinism (OCA) is a recessive condition caused mainly by mutations in the TYR and OCA2 genes involved in skin pigmentation. We previously screened the TYR and OCA2 genes in Colombian OCA families, identifying both known and novel mutations. Affected family members were found to be either homozygous or compound heterozygous for these gene mutations. Compound heterozygosity, where two different recessive alleles inherited from each parent lead to the expression of an autosomal recessive trait, poses a challenge in genetic diagnosis. Estimating the ancestry of these disease-associated variants, in conjunction with understanding the colonization history of admixed populations, can enhance the precision of association mapping in genetic studies. The aim of this study was to determine the ancestral origins of TYR and OCA2 mutations for OCA patients from two populations located in the Andes region of Colombia-Altiplano Cundiboyacense and Marinilla-Santuario. Comparison of OCA patients, and their unaffected relatives, with global reference populations showed a pattern of European and Native American admixture, with little African ancestry, for these two populations. Mutation-bearing TYR and OCA2 haplotypes from Colombian OCA patients were compared against haplotypes from Spanish, Native American, and Sephardic Jewish reference populations to infer their ancestral origins. For 12 OCA1 patients from the Altiplano Cundiboyacense region, 21 out of 24 mutated TYR haplotypes show Spanish origins, two show Native American origins, and one shows a Sephardic Jewish origin. The two Native American TYR haplotypes, and the single Sephardic Jewish haplotype, are all found in compound heterozygote patients, paired with the predominant Spanish TYR haplotype G47D. OCA in these three patients is a result of genetic admixture that brought together disease-causing mutations with distinct ancestral origins. Both OCA2 patients from the Marinilla-Santuario region show homozygous OCA2 mutations with a Spanish origin. These findings underscore the complexity of the genetic architecture of Mendelian disease in admixed American populations, with both consanguinity and admixture contributing to the risk of autosomal recessive OCA in Colombia.
常染色体隐性疾病通常与显示共同祖先起源的纯合突变有关，并且常与近亲结婚有关。然而，在多样化的混合人群中，越来越多的复合杂合子被发现。眼皮肤白化病（OCA）是一种主要由参与皮肤色素沉着的 TYR 和 OCA2 基因突变引起的隐性疾病。我们之前在哥伦比亚的 OCA 家族中筛选了 TYR 和 OCA2 基因，鉴定了已知和新的突变。受影响的家族成员被发现是这些基因突变的纯合子或复合杂合子。复合杂合性，即从每个父母那里遗传的两个不同的隐性等位基因导致常染色体隐性性状的表达，给遗传诊断带来了挑战。结合混合人群的殖民历史，估计这些与疾病相关的变体的祖先起源，可以提高遗传研究中关联图谱的精度。本研究的目的是确定来自哥伦比亚安第斯地区两个群体（Altiplano Cundiboyacense 和 Marinilla-Santuario）的 OCA 患者的 TYR 和 OCA2 突变的祖先起源。与全球参考人群相比，OCA 患者及其未受影响的亲属显示出欧洲和美洲原住民混合的模式，这两个群体的非洲血统很少。来自哥伦比亚 OCA 患者的携带突变的 TYR 和 OCA2 单倍型与西班牙、美洲原住民和塞法迪犹太人参考人群的单倍型进行比较，以推断其祖先起源。在来自 Altiplano Cundiboyacense 地区的 12 名 OCA1 患者中，24 个突变的 TYR 单倍型中有 21 个显示西班牙起源，两个显示美洲原住民起源，一个显示塞法迪犹太人起源。两个美洲原住民 TYR 单倍型和一个塞法迪犹太人单倍型均存在于复合杂合患者中，与主要的西班牙 TYR 单倍型 G47D 配对。这三个患者的 OCA 是遗传混合的结果，将具有不同祖先起源的致病突变结合在一起。来自 Marinilla-Santuario 地区的两个 OCA2 患者均表现出 OCA2 突变的纯合子，具有西班牙起源。这些发现强调了混合美洲人群中孟德尔疾病遗传结构的复杂性，近亲结婚和混合都增加了哥伦比亚常染色体隐性 OCA 的风险。
