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Skip to 0 minutes and 29 seconds Today we are going to talk on the position of humans in nature, and nothing better for that to have our interview with Tomàs Marquès-Bonet. He is ICREA research professor at University Pompeu Fabra and director of Institute of Evolutionary Biology; a Joint center between the Spanish Research Council and the Pompeu Fabra University. Tomàs did his PhD in Barcelona, the moved to the University of Washington in Seattle, USA. And came back to Barcelona to settle his own lab, mostly focusing on the genetic variation in the great apes. In the same way that we now have a deep knowledge on human populations and genome variation, he has been studying [stirring?] up the field doing a similar work for all the ape species.

Skip to 1 minute and 27 seconds And now we have much better knowledge thanks to his work in all these species; chimpanzees, bonobos, gorillas and orangs. And here we are today, at the Barcelona Zoo, in front of the Chimpanzees. In this interview we are going to focus on what we have learned for humans; both for the apes by studying the genome and the variation on the genome in our closest relatives. Tomàs, you have done a very extensive study of genomes of the great apes. Do these studies intend to understand the species, or these studies also help to understand ourselves? Both.

Skip to 2 minutes and 14 seconds So, the rationale that we use when we start -when it’s still today the most comprehensive analysis on genome variation on the apes- was to put human diversity in evolutionary context, right? So clearly one of the tools we have to understand evolutionary processes are comparative genomics, right? And to do that, you can do that with living species, that will be comparing human genomes with chimpanzee genomes, and finding in their genomes what do they share and what do they do not share to find lineage-specific molecular traits –that will be, for instance, one approach-; the other approach will be with non-living species like Neanderthals, for instance, ok?

Skip to 2 minutes and 59 seconds But clearly, what we start doing was to sequence a handful of each species, chimpanzees, bonobos, gorillas, orangutans… And then follow exactly the same methodological procedures, that in that case the major efforts to resequence human variations were doing at that time, and essentially just compare the patterns of diversity that we saw in humans and in the other species. And clearly, that was first, to study the differences between humans and the rest of the apes. However, of course, after you have this dataset of genomic variations per species -at species level, chimpanzees, gorillas and orangutans- we can start understanding or studying some of the molecular processes or demographic processes specific for each of the other species as well, of course.

Skip to 3 minutes and 52 seconds These species, you have shown us, that they are extremely similar to humans. This is something that sometimes is surprising, but does it surprise you? To know that the amount of similarities is very high, let’s say, 99 or 95 per cent, depending on how you measure it. Now it’s the perfect time to just, finally say, these number is wrong. It’s not wrong in the sense that it was not well done in the terms of calculation but, for some reason that totally skips my comprehension, it has become very popular for society, and we all scientists understood exactly the meaning of that number and it’s not the meaning that society has.

Skip to 4 minutes and 39 seconds So, if you allow me I will explain what this number means and what this number does not mean. So clearly between -let’s put, as a system- humans and chimpanzees, ok? Clearly they are far too different to be explained by 1% divergence. Which is the 99% identity and 1% divergence is the number that everyone has in their heads. And that is wrong. That is wrong. Why? When the first calculations of this number were done, that was back in 2005, there was one human genome and one chimpanzee genome. And in order to compare the difference, the very first thing you have to do is to find the pieces in each genome that are analogous, the pieces that you can compare.

Skip to 5 minutes and 27 seconds And then you can align one on top of each other, and say “ok, this base is the same, this base is the same, this base is different”. So notice two things. First, that not all the genome could be aligned between species; clearly more than 10 or 15% of the genome was not initially aligned. And second, this number only refers to point mutations, those mutations that only change one nucleotide;

Skip to 5 minutes and 54 seconds there are many more mutations up there: insertions, deletions, copy number variations, repeats… And that has never been accounted in this 1% of divergence. So clearly, today with the abilities and the knowledge we have today, this number will be, at least, one order of magnitude higher. That much? That much. The problem is that we cannot setup a fix number. Why? Because despite of our efforts and despite the technological advances, not a single genome, not even humans genomes, are completely finished form the first nucleotide to the last nucleotide. There’s still many regions that are not sequenceable and understandable today, and hence, we cannot go in there and make calculations of the difference.

Skip to 6 minutes and 40 seconds But for the rest of the genome if we now allow repeats, indels and other variations, the number will be at least 10% between the two species. That’s a huge number. Then, if you do that, we should also revise the amount of diversity within humans. I agree, I agree. I agree because exactly the same concern that I’ve applied between humans and chimpanzees will be the same between you and I, in this case that previously known one per thousand, right? In your studies of the apes you try to reconstruct the history, the demographic history, the evolutionary process of these species. Are there interesting surprises? Are they similar to humans?

Skip to 7 minutes and 24 seconds Yeah so, there are now statistical ways that even with a single genome and just looking for clusters of variation between the two chromosomes we can reconstruct back in time how many chimpanzees were out there, or how many humans, orangutans, whatever. And I will say there are two surprises that we found looking at the trajectory -the demographic evolutionary trajectory- of these species. First, if we compare the trajectories between humans and the rest of the great apes surprisingly it’s the gorillas the one that have the trajectory that is more similar to humans today, and not chimpanzees. Chimpanzees have had a trajectory that shows big expansions and contractions. To a magnitude that it’s at least three-fold that what has happened to our species.

Skip to 8 minutes and 17 seconds What time-frame are you talking? I’m talking about the last 2 million years. In the last 2 million years. So, clearly, there have been more expansions and contractions whereas humans and gorillas are more steady, more balanced in the terms of expansions and contractions. And the other thing that was really surprising –because it was the only species of great apes that shows that- is Sumatran orangutans. Sumatran orangutans show a very high number of effective population size, some redundant in variation and number of individuals, and suddenly, pretty much between 50.000 years ago and 100.000 years ago there is a total collapse of the population.

Skip to 8 minutes and 55 seconds It’s not a decline like it would seem with other species, it’s a total collapse in a very small period of time. And we have now papers that suggest that this could be related to a volcano eruption in the Sumatran Island. So, meaning that the genomic data allows the demographic reconstruction of these species, and they are showing traits very different from our own ancestors. Totally, totally. Not just that. These trajectories are not just interesting to study what happened in the past, these trajectories do leave a genomic footprint in their genomes.

Skip to 9 minutes and 33 seconds Meaning that, the mutation unload, the amount of variation they have that can be detrimental for the functioning of a cell, it does correlate very well with the past effective population size of this species, right? Meaning that, in principle, the higher the number of individuals, the more efficient the selection is, looking for this detrimental mutation and removing them from the population, but when there is such a drastic event, or for instance in mountain gorillas, where there are very few of them alive, we see an amount of detrimental mutation, which is superior to what we see in other species, right? This is related to a very interesting point, which is the amount of diversity within the species.

Skip to 10 minutes and 17 seconds And sometimes we think that humans, as we are that many, we should also be very different among us, which is not the case. No, no. In population genetics there is a term, which is effective population size, which is very easy to understand. It relates not to the census number –in humans it would be 7 billion- but the effective population size is a theoretical number to explain the minimum numbers of individuals that you will need to pass the genetic variation to the next generation. Just to make a very simple example, if we have a collection of aclonal cells, the census population size will be millions; but if they are clonal, the effective will be one.

Skip to 11 minutes and 1 second Because with one individual we have all the genomic variation. So in humans, it’s 7 billion of human beings today –that’s the census size- and the effective population size, that reviews the genetic diversity, it’s between 10.000 to 20.000. So very, very small number of individuals; that shows that we are, first, a very recent species; and second, that we are highly similar one to each other, of course. More than other species like the chimpanzees we have here. For instance, in chimpanzees it’s very entertaining, because there are in fact, 4 recognized taxonomically subspecies. And each of them has a very different effective population size.

Skip to 11 minutes and 42 seconds Some of them it’s very similar to us, because it’s very new and has been reduced to a very western part of central Africa. But the central population of chimpanzees is at least three times more variant in genomics, genetically speaking, than our species today. So, this is what we say sometimes that “humans are nearly clonal”. Your work has had also a very strong impact in understanding the structure of the genetic variation of ape species. And this is very important for conservation. To which extent conservation may really be helped by the study of the genomes?

Skip to 12 minutes and 28 seconds So, one of the things we like a lot in the lab is that, in this case, all this academic work translates in a very social application at two levels. We can work now in in situ conservation programs -in situ means in Africa-. Because still today one of the main problem of great apes, on top of deforestation, is illegal trafficking. And for illegal trafficking, still today the main problem is legislation; because all the confiscated animals, when they are captured in Europe, in Russia, in the United States, they have no clue where the animals come from. Because the airport, of course, is not a good hint.

Skip to 13 minutes and 8 seconds One of the real applications of our work is that we have shown that chimpanzees in Gabon are very different genetically than the animals on DRC [Democratic Republic of the Congo] or animals on Equatorial Guinea. Meaning that now we can reverse that; meaning that “give me a chimpanzee and I will be able to tell you the country of origin of this confiscated animal”. And then, we are now on the way to create the first statistic of where are the main problems of illegal trafficking and the problems of poaching. And then that will be the foundation for UNESCO and other supragovernamental entities, to change the legislation acting locally at very specific countries. That’s in situ.

Skip to 13 minutes and 52 seconds The other application is ex situ, the captive animals in Europe, for instance. These guys over here. Still today, zoos do a tremendous effort to try to keep pedigrees on all the animals; and when the animals are just changed among zoos, it’s all based on visual observations, because there were not genetic tools to know relatedness of the animals or the origin of the animals. So now, for the very first time, we are giving them the opportunity to use genetic tools to look at relatedness; and in that way, to improve the studbooks, which are, you know, the basic organization tool to know the pedigrees of all the animals over here. Now we can implant genetics on them.

Skip to 14 minutes and 37 seconds And also –if that’s interesting for them, and that’s for them to decide- in order to know the subspecies for all of these animals, and then when they are doing breeding programs, to take that into consideration into the movement of animals. OK, thank you very much Tomàs. We have seen today how important the genetic knowledge of our related species is; for them and for us.

Conversation with Tomàs Marquès-Bonet

Tomàs Marquès-Bonet is ICREA Research Professor at Universitat Pompeu Fabra and Director of the Institute of Evolutionary Biology, a joint center of the Spanish Research Council and Pompeu Fabra University, in Barcelona.

Concepts to clarify in conversation

1.- Comparative genomics (2.38)

This is a field of biological research within evolutionary biology in which the genomic features of different organisms are compared. It may include different genomic features, like DNA sequence, genes, gene order or others. For not very distant species the comparison of DNA sequences is the most used and interesting area, as there are only small amount of changes between the species. Comparative genomic approaches start with making some form of alignment of genome sequences and looking for orthologous sequences (sequences that share a common ancestry) in the aligned genomes and checking to what extent those sequences are conserved.

2.- Orthologous and homologous genes (5.26)

Two DNA sequences are called homologous is they have a shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry either because of a speciation event (orthologs), or because of a duplication event (paralogs) and then the copies are found within the same genome.

3.- Insertion, deletions, copy number variations (5.55)

Different types of variants found in the genome. Insertion, when there is the addition of one or more base pairs into the DNA sequence. Deletion, when a part of the sequence is lost. Copy number variation, when sections of the genome are repeated and the number of repeats in the genome varies between individuals in the population.

4.- Indels (6.44)

Insertions and deletions taken together.

5.- Mutation load (9.34)

It refers to the reduction of fitness (capacity to live and reproduce of the individuals) due to mutations that cause a detrimental phenotype that impairs or decreases either survival or reproduction. In general these variants (or mutations) are called deleterious or detrimental (min. 9.56). High genetic load may put a population in danger of extinction.

6.- Effective population size (9.46)

This concept is very well defined later in the interview.

7.- C.A.R. (13.16)

Central Africa Republic, territory with Eastern Chimpanzees (Pan troglodytes schweinfurthii).

8.- Studbooks (14.26)

This is a registry of the captive individuals of a species to assist in population management. In the zoo world, they are to document the pedigree and entire demographic history of each animal within a managed population. Imonitors births, deaths, parentage, individuals acquired from the wild, their location, and any transfers of individuals. Many endangered and vulnerable species have studbooks to coordinate management efforts and they are valuable tools to track and manage each individual as part of a single ex situ population.

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