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Sérgio Pena: Under the skin

The Minas Gerais geneticist proves that, at the cellular level, Brazilians look the same

Eugênio Sávio

No matter their skin color, most Brazilians who are white, Black or indigenous have paternal ancestors from Europe and maternal ancestors of African or American Indigenous origin. Within the over 20,000 genes in the human genome, skin color is determined by just 20 or 30 genes and is completely unrelated to an individual’s intellectual capacity. “Skin color is just a geographical adaptation. People are dark-skinned in all equatorial regions of the world, where it is sunnier,” claims geneticist Sérgio Danilo Junho Pena.

After a 12-year career as a physician, researcher, and university professor in the United States, England, and Canada, Pena began studying the genetic origins of the Brazilian people in the late 1980s. His work is known for proving that Brazil’s population has a trihybrid heritage, and that the relationship between skin color and ancestry is tenuous at best. This is illustrated by Rio de Janeiro samba artist Luiz Antônio Feliciano Marcondes—whose stage name, Neguinho da Beija-flor, celebrates his skin color. After being examined by Pena’s team, Marcondes found out he is 67.1% European and just 31.5% African.

In 2020, at the age of 72, the geneticist asked to retire from the Federal University of Minas Gerais (UFMG), but it was never in his plans to stop working. From his home, Pena follows the research developed by the group he established at the university and the work of his two genetic testing companies—one of which, Gene Lab, is run by his wife, Betânia, a cytogeneticist. They have one son, who lives in São Paulo, and four grandchildren. Pena talked to the editors of Pesquisa FAPESP via video chat as he eagerly awaits the end of the pandemic so he can go back to seeing his patients in person again. “I really miss the personal contact with my patients,” he shares.

Age 72
Field of expertise
Medical genetics
Federal University of Minas Gerais (UFMG)
Medical degree from UFMG (1970) and PhD in Human Genetics from the University of Manitoba, Canada (1977)
Published works
305 scientific articles and 6 books

You and two other UFMG professors, Fabrício Santos and Eduardo Tarazona-Santos, published a November 2020 paper in the American Journal of Medical Genetics about the genetic makeup of Brazil’s population. How does this work relate to your first study in this area, published in Ciência Hoje in April 2000?
The work we did later complemented, but did not contradict, the discoveries made at that time. We were the first to prove that Brazilians have a trihybrid heritage with sexual asymmetry. The Y chromosome, from the paternal lineage, comes predominantly from European colonists, while the mitochondrial DNA, from the maternal lineage, is mainly Indigenous or African. In Ciência Hoje, we showed there were countries with two distinct genetic profiles in Latin America: one group with a trihybrid population, such as Brazil, Colombia, and Venezuela, and another with a dihybrid population, such as Bolivia and Peru, where there was very little trading of enslaved Africans. Our results have been replicated and confirmed in several countries in South America, the Caribbean, and to some extent even in the United States. The US is peculiar in a way. When you look at the genetic makeup of North American Black individuals, one sees an introgression([incorporation) of European genes, mainly in the Y chromosome. But when you look at white people, you do not find the expected African mitochondrial inheritance. One of the reasons for this is how race is classified in the US: they base it on ancestry, not phenotypic criteria—or people’s appearance—as in Brazil. In the United States, a person is considered Black if they have African ancestry, regardless of their physical appearance. Thus, even people who look white can be socially categorized as Black. Since only individuals with no African ancestry are considered white, there is no trace of African genes in their genetic material. Furthermore, less than 1 million enslaved Africans were traded into the United States, while 4 to 5 million were taken to Brazil.

During the colonial and imperial eras in Brazil, miscegenation took place due to a power imbalance, correct?
Exactly. The Y chromosome was predominantly European, while the mitochondrial chromosome was mainly Indigenous, for two reasons. The first reason is that the Portuguese colonists did not bring their wives. The second reason is sexual exploitation, since relationships were certainly not consensual, generally speaking. No other country in the world has this much miscegenation. I have written before that Brazil was the meeting point of all the groups of the African diaspora around 100,000 years ago. Homo sapiens originated in Africa, then went on to Oceania, Asia, Europe, and finally the Americas. All peoples from these origins found each other again in Brazil.

How have ancestry analysis techniques evolved since you first began your work?
In 2003, we stopped working exclusively with the Y chromosome and mitochondrial DNA and began testing for autosomal inheritance, meaning almost the entire genome. With this approach, we proved that, in Brazil, the relationship between skin color and ancestry is tenuous at best. Under the skin, there are all types of mixed races. In 2007, in a study commissioned by the BBC of certain famous Black Brazilians, the issue of Rio de Janeiro samba artist Neguinho da Beija-flor (stage name for Luiz Antônio Feliciano Marcondes) came up. Even though he celebrates the color of his skin through his stage name, we found that he is 67.1% European and just 31.5% African. That was unexpected for him. But genetics is descriptive, never prescriptive. It is a scientific descriptor; it does not dictate what a person has to be. Identifying with one social group or another is a personal choice.

Your work with individuals from different regions of Brazil also dispelled some assumptions.
Yes. In Brazil, it was widely believed that phenotype alone could describe an individual’s ancestry. In the North and Northeast, where a higher number of people self-declare as brown, one might expect the population to be more mixed than in the South, where there are more white people. But, when analyzing their DNA, we found these two regions have similar genetic backgrounds. This is due to the almost 6 million European immigrants that arrived in Brazil from 1870 onward. Their arrival was due to racism, because the Brazilian government of that time only accepted Europeans, rejecting Africans and Asians. This discrimination began with Dom Pedro II, who let himself be influenced by racist theories that preached the idea of “whitening” Brazil. They wanted to bring in more white people in order to make Brazil a country of white people, not of people of color. They did not succeed at the phenotype level, but they did at the genome level, because the genome of Brazilians is predominantly of European origin. As a result of this intense European immigration, Brazilians generally ended up being more or less 70% European, regardless of the region. The predominance of brown people in the North and Northeast stems from a geographical phenomenon: people there are more exposed to sunlight. We found white-skinned residents of Porto Alegre (in the southern state of Rio Grande do Sul) that had the same amount of African ancestry as brown-skinned people from the North. What makes them lighter- or darker-skinned is an environmental factor: sunlight. The only acceptable criterion for skin color in Brazil is self-declaration. There are no objective criteria for skin color, especially when considering environmental and cultural factors.

We found white-skinned residents from Porto Alegre that had the same amount of African ancestry as brown-skinned people from the North

What are the consequences of this miscegenation?
It is due to miscegenation that, in Brazil, there are white people with sickle cell anemia—a genetic disease characteristic of regions where malaria is highly prevalent, such as much of Africa—and black or brown people with cystic fibrosis, a genetic disease typical to Europeans. Brazil’s population consists of 220 million equally different people. We hoped that, by showing the genetic makeup of Brazilians, we could reduce racism, but I’m not sure we succeeded. People shouldn’t be classified into skin color or sex. Men and women should have equal contributions in society and be treated equally. There should be no sexism or homophobia, which go hand in hand with racism. Out of the 20,000 genes in the genome, only 20 or 30 determine skin color. As I said before, these genes linked to skin color have nothing to do with intellectual capacity. Skin color is merely a geographical adaptation. People are dark-skinned in all equatorial regions of the world, where it is sunnier.

Why is skin color so important in Brazil?
In the sixteenth century, the nations involved in the slave trade—England, Spain, and Portugal—were Christian. Because it was against their religion for Christians to treat others as lesser, they made up a myth that Africans were inferior to whites because they were descendants of Ham, one of Noah’s sons. Noah once became drunk on wine and fell asleep naked inside his tent. Ham saw that his father was naked and ran out to tell his two brothers. For this, Noah cursed Canaan, son of Ham: “A servant of servants shall he be unto his brethren.” This served as a moral justification for the trading of enslaved Africans, which was highly profitable. England’s industrial and scientific revolutions, for example, were largely funded by the slave trade. Unfortunately, science has yet to eliminate the value judgement of individuals based on their skin color. According to genetics, there is no such thing as human races. Racism is a cultural construct—since we made it, we can and should unmake it. We can and must build a society without races.

Have geneticists ever been racist, historically?
Only when the concept of race is profitable to them. Unfortunately, scientists are subjugated to whoever owns the money. In the nineteenth century, they came up with racist theories to please politicians, who controlled the money. Sadly, nowadays we know that some highly regarded geneticists, such as James Watson (who helped discover the structure of the DNA molecule in 1953 and one of the winners of the Nobel Prize in Physiology or Medicine in 1962), are racists. Watson has made several statements recently saying that he believes Africans are intellectually inferior, which is ridiculous.

What motivated you to study the genetic roots of the Brazilian people?
I spent 12 years abroad. I did a medical residency in the United States and one in Canada, where I also finished my PhD in human genetics. I then got my post-doc in England, before returning to Canada and becoming a university professor there. One day, my wife said, “Enough. Let’s go back to Brazil.” I wisely agreed. We returned in 1982 and, as a geneticist, I began working with paternity and HLA (human leukocyte antigens, which are responsible for the body’s response against viruses, bacteria, and protozoa) tests. Because of the limitations of HLA, we adopted the DNA methodology in 1988. In fact, we were the first to perform DNA paternity tests in Brazil and in Latin America. Around the same time, the polymerase chain reaction (PCR) technique was invented, and we were one of the first in the world to use it to characterize genetic polymorphisms of the human Y chromosome. We have used PCR to study the genetics of the indigenous peoples of America, from Patagonia to the United States. We discovered a very high homogeneity of the Y chromosome: more than 90% of them belonged to the same lineage. We were the first to identify this trait, which results from a founding effect. The first group of humans to arrive in the Americas brought a Y-chromosome lineage that spread to all countries on the continent. Fabrício Santos, who was my PhD student in the early 1990s, later used the genetic characteristics of this founding Y chromosome to show that indigenous peoples from all three Americas descended from individuals from central Siberia. Around the year 2000, on the 500th anniversary of the arrival of Europeans in America, we employed the mitochondrial DNA PCR methodology to conduct a study on both paternal and maternal lineage markers to characterize the ancestry of white Brazilians. We then found that the Y chromosome of white Brazilians was mainly European, while the mitochondrial DNA was predominantly Indigenous or African. We then extended the work to cover biparental genetic markers in human autosomes. At the time, we were studying less than 100 markers; nowadays, we study hundreds of thousands of them. But our conclusions have remained the same. One key discovery is that the various ancestral origins are not uniformly distributed in the genome. The genes are grouped in blocks, called haplotypes. In the genome of the Brazilian people, the blocks of genes with Indigenous, African, and European origins are segregated, forming a sort of mosaic. Today, we are able to see where each chromosome segment comes from—whether it is African, European, or Indigenous American. It is a technological refinement called local ancestry.

Personal archives Pena between James Watson and Francis Crick (right) in Paris, 1973Personal archives

What was your role in the first genome sequencing projects in Brazil?
In 1992, as president of the Brazilian Society of Biochemistry, I led a conference in Caxambu, Minas Gerais, where we brought together nearly 100 foreign pioneers in human genomics. Since the Americans and Europeans had already been sequencing the human genome, we decided to use the same techniques to study Schistosoma mansoni, which causes schistosomiasis, and Trypanosoma cruzi, which causes Chagas disease. They were not as interesting as Homo sapiens, but they were the two most important parasitoses in Brazil, and they enabled us to study the DNA of parasite populations. There were several theories about Chagas disease—some advocating that it was the parasite itself that caused it, others that the parasite led to an autoimmune disease. By studying different forms of Chagas disease (cardiac or gastrointestinal), we found different parasite strains focused on one organ or the other. The parasites found in the esophagus were genetically distinct from the protozoa found in the hearts of cardiac patients.

What was your work with S. mansoni like?
One of the guest speakers at the 1992 conference was Craig Venter (American biochemist and entrepreneur; a pioneer in the private sequencing of the human genome), who was developing a sequencing technique called EST (Expressed Sequence Tags). I had been collaborating with the British biochemist Andrew Simpson, who had worked with schistosomiasis in England and was working at FIOCRUZ (Oswaldo Cruz Foundation), in Belo Horizonte. This was the first official project involving genomic methodology in Brazil, and it was very successful. Simpson then moved to São Paulo and led the sequencing projects for the genome of the bacterium Xylella fastidiosa and for the Human Cancer Genome (both funded by FAPESP).

What is your opinion on the sequencing of the human genome, completed in 2003?
There are great things about the genome. For example: 8% of the human genome is made up of endogenous retroviruses, which have inserted their genetic material into the human DNA. Much like archaeologists, we can dig up genomic fossils, elements that were useful in the past and are kept simply because the genome doesn’t throw anything away. This is why I don’t like the expression junk DNA. I prefer clutter, because while you throw away junk, you keep clutter around because it may be useful in the future. But since we thought humans were the apex of evolution, it was humbling to find that we had the same number of genes as certain nematode worms or fruit flies. There are amoebae whose genomes are hundreds of times larger than the human genome. What saved our wounded pride a bit was finding that, through a process called alternative editing, we can generate hundreds of thousands of different transcripts from the 20,000 genes in the genome. Another key achievement was changing the very concept of what a gene is. We had a very simple view of genes as being a segment of DNA capable of encoding a protein. But we found they are much more complex than that. We discovered there are several types of genes, not all of which encode proteins. Some of them encode RNAs, which won’t be translated into proteins but will have roles of their own—like ribozymes, which are similar to enzymes.

We hoped that, by showing the genetic makeup of Brazilians, we could reduce racism, but I’m not sure we succeeded

In 2001, when the draft of the human genome came out, you said we were starting to build the medicine of the 21st century. Where does genome-based medicine stand now, 20 years later?
Precision medicine, which is essentially about treating patients, not diseases, is still in its infancy. Some groups of researchers, mainly in the United States, are studying DNA mutations of tumor cells to improve treatment. This means a patient with an intestinal tumor could theoretically be subjected to the same treatment as a patient with lung cancer—if the mutational event that originated these neoplasms is the same. Today, it is relatively easy to find gene variants associated with diseases, which does not mean that they actually always cause them. In genetics, we have something called penetrance, which formally means the proportion of individuals that have the variant of a disease-causing gene that actually develops the disease. Most genes are not 100% penetrant. This is why someone can have a pathogenic mutation of a gene and not develop the disease. It seems that environmental factors and the other 20,000 genes in the genome can modulate the altered gene and make it inactive. Studies on the exome (stretches of DNA that induce protein production) and genome allow us to diagnose diseases caused by a single gene (see Pesquisa FAPESP issue nº 259). But most illnesses, such as heart disease, diabetes, hypertension, and mental disorders, are polygenic and result from both genetic and environmental predispositions.

Twenty years ago, there was a lot of talk that geneticists needed to study history, sociology, and anthropology. Is this still a concern?
It is true that, to understand human genetics, one must know sociology, anthropology, and history. The human sciences open the mind and show that, on top of our genetic heritage, we also have a cultural heritage. Back in the Ciência Hoje article, I said I was simply demonstrating scientifically what Gilberto Freyre (sociologist, 1900–1987), Paulo Prado (jurist, 1869–1943), Sérgio Buarque de Holanda (historian, 1902–1982), and Darcy Ribeiro (anthropologist, 1922–1997) had pointed out long before. With genetics, their work makes much more sense. When we studied the Y chromosome of Brazilians from the North, Northeast, South, and Southeast, in Amazonian individuals there was a high incidence of a Y-chromosome haplotype commonly found in Middle Eastern individuals. By looking up historical information, I found there was a group of Moroccan Jews who had immigrated to the Amazon and became part of riverine populations. In Brazil, the Y chromosome of European origin comes mainly from southern Europe, but in the state of Pernambuco there is a high amount of northern European Y haplotypes, which is probably a result of the Dutch invasion. The combination of genetics, history, anthropology, and linguistics is fascinating. I’m not sure whether genetics students and researchers are paying attention to the humanities, but I heard our Ciência Hoje article is being studied in some sociology and political science programs.

With the genome, it was humbling to find that we had the same number of genes as certain worms or fruit flies

You founded and managed two companies while working at the university. Did your fellow professors disapprove?
Yes, because in their view you were either a researcher or a clinician. I decided I’d be both. In Canada, while I was a university professor, I also had my own research lab and my clinic within the same hospital. This was not a thing here. Soon after I returned to Brazil, at the age of 35, I became a full professor of biochemistry—and I opened a clinic. The university staff were furious: “How can a clinician also be a tenured professor as department chair?” Many were against it, but then I became a kind of model of integration between companies and the university, which is a trend nowadays. But to achieve this I had to work two eight-hour shifts a day. I was able to combine the two activities because I was able to use business management techniques in the university and scientific criteria in my company.

How are your companies doing?
Both companies are achieving great success at the frontier of knowledge: Laboratório Gene – Núcleo de Genética Médica, which focuses on human genetic testing and diagnoses, and Gene-Genealógica, which offers cattle and sheep parentage tests. Neither was created to be big, but rather to be innovative. We have been doing many interesting things, such as clinical molecular diagnostics and prenatal genomics. We have introduced a number of practices, including genomic studies on miscarriage material and on fetuses with ultrasound abnormalities. We are working on diagnosing recessive diseases in horses, with the goal of identifying heterozygous healthy animals with unwanted mutations that prevent them from becoming breeders. This way, we can genetically improve herds.

How has your life been during the pandemic?
My life has changed little. I already worked from home a lot, managing the three laboratories from my computer—the one at the university plus the two companies. The only difference is that I stopped seeing patients in person when the pandemic started, but I intend to begin seeing them again as soon as possible. I really miss the personal contact with the patients. This is what motivates me. Remote genetic counseling works, but once I stop seeing the patient, several facets of medicine lose their meaning.