It is still not clear when and where modern humans, referred to as anatomically modern humans by palaeontologists, developed.

According to the widely accepted “out-of-Africa” migration model, the first anatomically modern humans first lived in south and east Africa, subsequently spreading to the entire continent in a process that took several ten thousands of years and eventually reaching Europe about 30,000 years ago. In Europe, these modern humans displaced the Neanderthal (Homo neanderthalensis) as well as other species of the Homo genus and were eventually found on all continents. This means that modern humans have diverged not that long ago and it also explains the low number of genetic differences among humans. Both genetic data gained from the comparison of mitochondrial DNA as well as fossil records reinforce the out-of-Africa theory.

According to a recent paper published in the journal Nature, it was exactly this group of African humans that left traces in the genes of today’s Europeans. Lohmueller and his colleagues investigated more than 10,000 DNA sequences of 20 European Americans and 15 African Americans. They mainly concentrated on the distribution of what are generally known as single nucleotide polymorphisms (SNPs for short). SNPs are single-nucleotide substitutions of one base for another that occur in more than one percent of the general population. Such a comparison only makes sense if the populations compared have some common genetic traits despite the fact that every human being has their own specific set of genes. That is why some SNPs are found in both African and European Americans and others are found in one group.

Due to the redundancy of the genetic code - the fact that several base triplets code for the same amino acid – the exchange of a single nucleotide during gene expression leads to the same amino acid (synonymous exchange). The non-synonymous exchange of a nucleotide leads to the incorporation of a different amino acid.

Thanks to the support of Steffen Schmidt, project leader at the Max Planck Institute of Developmental Biology in Tübingen, the researchers were able to predict the effect of such non-synonymous SNPs. Schmidt developed a special computer algorithm that enabled the classification of amino acid exchanges. The classification was based on the following criteria: neutral exchanges that most probably did not affect the function of the protein and nucleotide exchanges that had either small or big effects on the function of the protein. Usually, the consequences of such effects are disadvantageous; for example, the enzyme will cease to be fully functional. Synonymous SNPs were regarded as having no effect.

The data showed that genetic diversity was lower in the European population than in the African population; however, there was a higher ratio of non-synonymous SNPs. Using Schmidt’s PolyPhen algorithm, the researchers found that the higher number of non-synonymous SNPs was due to the redundancy of harmful SNPs. Among these potentially harmful variations there are big differences in terms of disease risk. The effect on the health of Europeans is still unclear.

A small number of SNPs can accumulate in small populations and have a near-zero effect on their carriers. However, in larger populations, these SNPs are eliminated efficiently. That is why the researchers assumed that the higher ratio of non-synonymous SNPs in the European population correlated with the different effect of natural selection acting on the Africans who migrated from Africa and populated the rest of the world and those who remained in Africa. The researchers further assumed that these differences were due to the different demographic history of the two populations.

The researchers tried to simulate the observations using diverse demographic migration models. All models in which the populations experience what is known a bottleneck effect had a higher number of non-synonymous SNPs compared to models simulating constant or expanding populations. A genetic bottleneck refers to a population that consists of only a few individuals, therefore entailing the loss of genetic variation. The simulations showed that the variations with a slightly negative effect are mainly due to the subsequent expansion of the European population. Since in evolutionary terms this expansion happened only recently, the time elapsed has not been sufficiently long for the high number of deleterious effects to be eliminated by natural selection. This also explains why Africans have a higher variation. When the emigrating group separated from the larger group, only part of the gene pool was taken along.

The results of the study are not only interesting from the perspective of evolutionary theory - the technology used to classify amino acid exchanges is also important in the medical field. SNPs are the most frequent type of mutations in humans. The PolyPhen algorithm might be able to help detect disease-related alterations.

Steffen Schmidt did his doctorate in the area of bioinformatics at the University of Heidelberg in 2003. He has been project leader in the Department of Biochemistry at the Max Planck Institute of Developmental Biology in Tübingen since 2006, where he mainly focuses on the evolution and variability of proteins and their function.

Literature: Kirk E. Lohmueller, Amit R. Indap, Steffen Schmidt, Adam R. Boyko, Ryan D. Hernandez, Melissa J. Hubisz, John J. Sninsky, Thomas J. White, Shamil R. Sunyaev, Rasmus Nielsen, Andrew G. Clark & Carlos D. Bustamante: Proportionally more deleterious genetic variation in European than in African populations. Nature Vol 451, 21 February 2008.