Whole-genome database will help refine diagnosis of genetic diseases in Brazil

Whole-genome sequences of 1,171 elderly people living in São Paulo City were analyzed to detect mutations responsible for disease or that play a key role in healthy aging.

By Elton Alisson  |  Agência FAPESP – A database containing whole-genome sequences for elderly inhabitants of São Paulo City in Brazil, developed by 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), will be used to detect mutations that are responsible for genetic diseases found in the Brazilian population or that play a key role in healthy aging.

Datasets for individuals are already available to the scientific community for downloading on request, and aggregate data has been posted in recent years to the Online Archive of Brazilian Mutations (ABraOM). 

An analysis of the genomic data is reported in an article just published in Nature Communications.

A paper with preliminary results was posted in 2020 to bioRxiv, a preprint platform for articles on the biological sciences that have not yet been peer-reviewed (more at: agencia.fapesp.br/34628). 

“Since the data began to be made available, many researchers in Brazil and abroad have accessed the repository, demonstrating the importance of this initiative to the scientific community,” Mayana Zatz, a professor at IB-USP, told Agência FAPESP. Zatz is principal investigator at HUG-CELL, a Research, Innovation and Dissemination Center (RIDC) funded by FAPESP.

The database resulted from a groundbreaking whole-genome sequencing study of 1,171 elderly Brazilians, representing Latin America’s largest cohort for research on the DNA of older people.

Originally called Projeto 80mais, the research began in 2008 with a project to characterize the genomes of physically and cognitively healthy seniors, establish a genomic reference database for the Brazilian population, and contribute to a deeper understanding of the factors involved in healthy aging.

The subjects in this study had an average age of 71 and were unrelated. They were selected by researchers at the University of São Paulo’s School of Public Health (FSP-USP) from the cohort recruited for the longitudinal study of Health, Wellbeing and Aging (Saúde, Bem-estar e Envelhecimento, SABE), which is supported by FAPESP.

SABE began in 2000, with Maria Lúcia Lebrão and Yeda Duarte as principal investigators. Both are professors at FSP-USP. 

SABE investigates the health and living conditions of people aged 60 and over in São Paulo and six other cities of Latin America and the Caribbean via interviews, assessments, and medical examinations. “The study is representative of the elderly population of São Paulo because it’s based on the municipal census of the city and includes people in all income groups,” Zatz said.

Highly mixed population

The subjects were selected for whole-genome sequencing because they had passed the age at which clinical manifestations of several aging-related diseases such as Alzheimer’s and Parkinson’s typically begin.

Because they live in São Paulo, Brazil’s largest city, they also represent the genetic diversity of the Brazilian population, which is highly mixed in terms of ethnicity and ancestry, Zatz explained. “São Paulo’s population is the most admixed of any Brazilian city,” she said. “It includes many descendants of immigrants from different continents, such as Europe, Asia and Africa, as well as natives of other states and countries.”

The considerable genetic diversity of the study sample contrasts with the coverage of international genomic databases, which is predominantly European. The research identified some 2 million genetic variants never before described in major public databases, for example.

“This has to do with the fact that the coverage of international databases mainly reflects the European reference genome. This number of novel genetic variants we found, in the range of 2 million, may decrease as the other big repositories begin to include under-represented populations like Brazil’s,” said Michel Naslavsky, a professor at IB-USP and first author of the article.

More diversity in international genomic databases will also improve the accuracy of genetic tests for populations as highly mixed as Brazil’s and those of other Latin American countries, the authors argue.

Analysis of the elderly people’s genomes in the Brazilian database shows that they carry genetic variants classified in European databases as pathogenic but do not manifest the diseases associated with these mutations. “One of the hypotheses we’re raising to explain this is that genetic variants hitherto classified as pathogenic may be expressed differently according to whether the individual’s genetic background is European or of mixed ancestry, for example,” Naslavsky said.

The researchers also found the subjects in the study to be bearers of variants associated with recessive disorders frequently seen in both Europeans and Africans, such as cystic fibrosis. The frequency of heterozygous individuals (people with a recessive variant) can be used to estimate the incidence of these disorders in the population. “In the case of the Brazilian population, we reckon the incidence of cystic fibrosis is one per 10,000 births,” Zatz said. “This information is very important to public programs of genetic counseling for couples of reproductive age on the risks of having children with severe genetic diseases.”

Analysis of the seniors’ genomes also enabled the researchers to detect novel variants of genes in the human leukocyte antigen (HLA) complex, which encodes proteins responsible for permitting the recognition of pathogens and regulating the immune system. These genes are known to be the most variable and diverse of all in the human genome and hence hard to analyze.

Using a special technique, they located more than 140 alleles from HLA genes never described before. Findings such as this are germane to studies on susceptibility or resistance to infection by a wide array of pathogens, including SARS-CoV-2.

The article “Whole-genome sequencing of 1,171 elderly admixed individuals from São Paulo, Brazil” is at: www.nature.com/articles/s41467-022-28648-3.