RESUMEN
Studies examining genetic conditions common in Latin America are highly underrepresented in the scientific literature. Understanding of the population structure is limited, particularly Chile, in part due to the lack of available population specific data. An important first-step in elucidating disease mechanisms in Latin America countries is to understand the genetic structure of isolated populations. Robinson Crusoe Island (RCI) is a small land mass off the coast of Chile. The current population of over 900 inhabitants are primarily descended from a small number of founders who colonized the island in the late 1800s. Extensive genealogical records can trace the ancestry of almost the entire population. We perform a comprehensive genetic analysis to investigate the ancestry of the island population, examining ancestral mitochondrial and Y chromosome haplogroups, as well as autosomal admixture. Mitochondrial and Y chromosome haplogroups indicated a substantial European genetic contribution to the current RCI population. Analysis of the mitochondrial haplogroups found in the present-day population revealed that 79.1% of islanders carried European haplogroups, compared to 60.0% of the mainland Chilean controls from Santiago. Both groups showed a substantially lower contribution of indigenous haplogroups than expected. Analysis of the Y chromosome haplogroups also showed predominantly European haplogroups detected in 92.3% of male islanders and 86.7% of mainland Chilean controls. Using the near-complete genealogical data collected from the RCI population, we successfully inferred the ancestral haplogroups of 16/23 founder individuals, revealing genetic ancestry from Northern and Southern Europe. As mitochondrial and Y investigations only provide information for direct maternal and paternal lineages, we expanded this to investigate genetic admixture using the autosomes. Admixture analysis identified substantial indigenous genetic admixture in the RCI population (46.9%), higher than that found in the Santiago mainland Chilean controls (43.4%), but lower than a more representative Chilean population (Chile_GRU) (49.1%). Our study revealed the Robinson Crusoe Island population show a substantial genetic contribution for indigenous Chileans, similar to the level reported in mainland Chileans. However, direct maternal and paternal haplogroup analysis revealed strong European genetic contributions consistent with the history of the Island.
RESUMEN
Background: Robinson Crusoe Island is a geographically and socially isolated settlement located over 600 km west of the Port of Valparíso, Chile. An unusually high incidence (30%) of the Chilean equivalent of developmental language disorder (in Spanish, trastorno especifico de lenguaje (TEL)), has been reported in Islander children, with 90% of these affected children found to be direct descendants of a pair of original founder-brothers, therefore strongly suggesting a shared genetic basis. Aim: This study reports a comprehensive examination of 34 genes that have been previously directly implicated in language-related mechanisms. It utilises whole-genome sequencing to investigate potential underlying variants in seven TEL affected and 10 unaffected islanders. The aim was to identify the underlying genetic cause of the TEL phenotype under two inheritance model paradigms; Mendelian monogenic and complex susceptibility. Subjects and methods: A targeted candidate gene approach was used to look for rare, shared variants that may underlie the diagnosis of TEL in a Mendelian genetic model. This study tested whether an overall burden of rare variants is enriched in individuals affected by TEL or with Islanders related to the founder-brother lineage. It further examined if any variants segregate with affection status or with founder-brother-related status and, therefore, may increase risk of developing a language disorder as part of a complex model. Finally, gene-based tests were performed to evaluate relationships between combined variation across candidate genes and TEL affection status. Results: No single pathogenic rare variant segregated with either affection or founder-related status within the 34 candidate genes. Additionally, no evidence was found of an overall increased variant burden in TEL individuals compared to those with TLD. Gene-based analysis found no clear association between the combined effects of variants across the 34 genes and affection status or founder-brother-relatedness. Conclusion: The high prevalence of language disorders found on Robinson Crusoe Island is not caused by either a shared high-impact variant, or an increased burden of variants within candidate genes previously implicated in language disorders. We have comprehensively tested for 'low hanging fruit' in genes implicated in language disorders. Therefore, the underlying cause of TEL on Robinson Crusoe lies outside of these known language disorder genes, or within a complex susceptibility model.