By Elton Alisson | Agência FAPESP – Researchers affiliated with the Human Genome and Stem-Cell Research Center (HUG-CELL) at the University of São Paulo’s Institute of Biosciences (IB-USP) in Brazil have completed the whole-genome sequencing of 1,171 elderly inhabitants of São Paulo, Brazil’s largest city.
By analyzing the data, now housed in the open-access repository ABraOM, scientists will be able to identify genetic mutations responsible for diseases, estimate their incidence in the Brazilian population, and find variants that can help assure healthy aging, among other applications.
The results of the study are published on bioRxiv, a preprint platform for articles on the biological sciences that have not yet been peer-reviewed.
ABraOM is the Portuguese-language acronym for Online Archive of Brazilian Mutations. “It’s Latin America’s largest database of DNA for elderly people and for a population as ethnically mixed as Brazil’s, resulting from research begun over ten years ago,” Mayana Zatz, a professor at IB-USP and HUG-CELL’s principal investigator, told Agência FAPESP.
HUG-CELL is one of the Research, Innovation and Dissemination Centers (RIDCs) funded by FAPESP.
The participants were selected by researchers at USP’s School of Public Health (FSP) from the cohort studied in the Survey on Health, Wellbeing and Aging, or SABE in Portuguese. They were unrelated and their average age was 71.
Begun in 2000, SABE is supported by FAPESP and led by Yeda Duarte, a professor at FSP-USP. It is a multiple-cohort longitudinal study of the health and living conditions of people aged 60 and older in seven cities of Latin America and the Caribbean, including São Paulo, based on interviews, assessments, and medical examinations.
“The study is representative of the elderly population of São Paulo because it’s based on the municipal census and includes people in all income groups,” Zatz said.
The sample was selected for whole-genome sequencing because the subjects concerned had passed the age at which clinical manifestations of several aging-related diseases such as Alzheimer’s and Parkinson’s typically begin, she explained.
Based on their analysis of the genomes of these elderly inhabitants of São Paulo, who included descendants of immigrants from different continents, the researchers identified almost 76 million genetic variants, some 2 million of which are not described in any genome database internationally.
A possible explanation for this gap is that highly mixed populations like Brazil’s are under-represented in these genome databases, which mainly hold genetic data for European populations.
The lack of diversity in the world’s genome databases tends to limit access by people of non-European descent to the benefits of precision medicine and accurate testing, potentially increasing health disparities, according to the authors of the article on the study.
“The excessive number of variants not described shows that our parental populations aren’t represented in these databases and reaffirm the importance of sequencing the genomes of Brazilians specifically in order to reduce representative bias in the world’s genome databases,” said Michel Naslavsky, a professor at IB-USP and first author of the article.
Analysis of the genetic ancestry of the elderly people in the sample revealed considerable variability, ranging from a single ancestry to a mixture of two or more, with European, African, Amerindian, and East Asian predominating in this order.
This genetic diversity contrasts starkly with the homogeneity found in countries like the United States, where (despite the existence of descendants of Africans, Amerindians and Asians) people with two or more ethnic ancestries are relatively infrequent, Naslavsky said.
“Americans with this rare mixture are classified as Latino in US genome databases, but actually most are Mexican and don’t have the same genetic ancestry profile as the population of Brazil or other Latin American countries,” he added.
The researchers also identified some 2,000 novel mobile elements (insertions that can move around the genome), over 140 novel alleles from HLA genes, characterized by a wide diversity of forms and alleles, and genomic segments totaling 60-70 million base pairs absent from sequences produced to date, or 2% of the sequences in the human genome, which comprises 3 billion base pairs. While it may seem small, Naslavsky mused, this amount of unreferenced genomic regions corresponds to a significant proportion of the genome not yet in the world’s genetic databases and could explain the occurrence of certain diseases while telling the story of this population’s origins.
“We’re enriching the reference genomes with data for the Brazilian population,” he said. “From now on, whenever Brazilians’ genomes are sequenced it will be possible to align them with the global human reference genome and our own dataset.”
To demonstrate the clinical utility of the research, the authors compared almost 400 gene mutations identified in the elderly subjects with those labeled pathogenic in public gene databases and checked whether they corresponded to this classification.
“The comparative analysis led to a reclassification of more than 40% of the mutations and showed that some may have a less significant effect than previously supposed,” Naslavsky said.
The researchers also selected mutations associated with autosomal recessive diseases identified in the sample to estimate their incidence in the Brazilian population. Among these were cystic fibrosis (more common among Europeans), sickle cell anemia (more prevalent among Africans), deafness associated with the gene GJB2, and familial Mediterranean fever. Autosomal recessive diseases are caused by two altered copies of the same gene, one inherited from each parent.
In the case of cystic fibrosis, for example, incidence is estimated at 1 in every 2,000 newborns in Europe and 1 in 10,000 in Brazil. “The incidence of this disease is higher in Europe because the causative mutation is more common among whites. It’s rarer in Brazil, where the population is much more ethnically mixed,” Zatz explained.
According to the study, GJB2-related deafness and familial Mediterranean fever are the autosomal recessive diseases that occur most frequently among Brazilians, probably owing to Iberian, Mediterranean, and Middle Eastern genetic contributions.
“Besides their importance to precision medicine, the findings show that whole-genome sequencing can contribute to the formulation of public health policy by helping to estimate how many people may be born with genetic diseases in a given population,” Naslavsky said.
The article “Whole-genome sequencing of 1,171 elderly admixed individuals from the largest Latin American metropolis (São Paulo, Brazil)” by Michel S. Naslavsky, Marilia O. Scliar, Guilherme L. Yamamoto, Jaqueline Yu, Ting Wang, Stepanka Zverinova, Tatiana Karp, Kelly Nunes, José Ricardo Magliocco Ceroni, Diego Lima de Carvalho, Carlos Eduardo da Silva Simões, Daniel Bozoklian, Ricardo Nonaka, Nayane dos Santos Brito Silva, Andreia da Silva Souza, Heloísa de Souza Andrade, Marília Rodrigues Silva Passos, Camila Ferreira Bannwart Castro, Celso T. Mendes-Junior, Rafael L. V. Mercuri, Thiago L. A. Miller, Jose Leonel Buzzo, Fernanda O. Rego, Nathalia M. Araújo, Wagner C. S. Magalhães, Regina Célia Mingroni-Netto, Victor Borda, Heinner Guio, Mauricio L. Barreto, Maria Fernanda Lima-Costa, Bernardo L. Horta, Eduardo Tarazona-Santos, Diogo Meyer, Pedro A. F. Galante, Victor Guryev, Erick C. Castelli, Yeda A. O. Duarte, Maria Rita Passos-Bueno and Mayana Zatz can be read at: www.biorxiv.org/content/10.1101/2020.09.15.298026v1.