A new analysis of more than 4,000 ancient and contemporary human genomes

A new study of over 4,000 ancient and modern human genomes reveals how common such "founder events" were throughout human history. A founder event occurs when a small number of ancestral individuals give rise to a large proportion of the population, often as a result of war, famine, or disease, but also as a result of geographic isolation — on islands, for example — or cultural practices, such as among Ashkenazi Jews or the Amish.

human genomes
CAPTION Using modern and ancient DNA, UC Berkeley researchers calculated when population bottlenecks occurred for hundreds of groups around the world and throughout recent human history. The colors represent how many generations the bottleneck or founder event came before the individuals whose DNA was sequenced (human genomes). Rémi Tournebize, University of California, Berkeley

More than half of the 460 groups represented by these individuals had a population bottleneck in the past, which reduced genetic diversity and likely increased the incidence of recessive hereditary diseases.

The study, conducted by population geneticists at the University of California, Berkeley, is the first comprehensive look at founder events across a broad swath of human populations over the last 10,000 years or so, pinpointing when these events occurred.

The findings, according to the authors, will be useful not only to archeologists and historians tracking population movement and mixing around the world but also to scientists and doctors studying human genetic variation. Inbred genetic diseases have assisted scientists in discovering many disease-causing mutations in the human genome and the causes of numerous genetic and inherited diseases.

"Genomic data is really powerful because it tells us about our history at various time scales, and you can look at how closely related different individuals are to each other," said senior author Priya Moorjani, an assistant professor of molecular and cell biology at UC Berkeley. "However, it also tells us about functionally important bits of DNA that can cause diseases." As a result, they become quite important to study from a biomedical standpoint."

Many of the populations represented by individuals in the sample were or are far more inbred than ethnic Ashkenazi Jews, who some scientists estimate once dwindled to a population of a few thousand people around 1,000 years ago. The Onge, a group in the Indian Ocean's Andaman Islands, experienced a population bottleneck ten times that of Ashkenazi Jews, and now numbers only about 100 people.

The researchers discovered that many Native American populations, as well as groups from Oceania and South Asia, were experiencing severe population bottlenecks. Some are associated with known historical events; for example, the residents of Rapa Nui (Easter Island) experienced a founder event around 260 years ago, coinciding with European migration to the island.

Others correlate well with known human movement into an area as well as changing cultural artifacts and practices. Anatolian farmers and Eurasian steppe pastoralists, for example, moved into Europe between 4,000 and 10,000 years ago and intermarried with existing European hunter-gatherers.

"The first surprise was that evidence for founder events was found in more than half of the groups we surveyed," Moorjani said. "So, it's not just Ashkenazi Jews or Finns who have a unique history, but many contemporary populations have had strong founder events — in fact, stronger founder events than these two groups, such as several contemporary South Asian groups, hunter-gatherers, or island populations." Many of these groups would be critical in prioritizing functional studies. We've learned so much about genetic variation from groups like Ashkenazi Jews and Finns that the potential for discovery is enormous if we can expand these studies to other global populations."

Moorjani, former UC Berkeley undergraduate Gillian Chu, and first author Rémi Tournebize, who is now a postdoctoral fellow at the Instituto Gulbenkian de Ciência in Oeiras, Portugal, published their findings in the journal PLOS Genetics today (June 23).

Working with diverse ancient DNA

The analysis was made possible by ASCEND (Allele Sharing Correlation for the Estimation of Non-equilibrium Demography), a genomics analysis program developed by Tournebize and Moorjani specifically to analyze partial genome sequences, particularly ancient DNA. This DNA is typically extracted from hundreds to thousands of years old bones or teeth that represent not only our Homo sapiens ancestors but also other human groups such as Neanderthals and Denisovans.

Typically, such DNA is damaged, allowing only a portion of the individual's genome to be sequenced. However, because human genomes contain approximately 3 billion base pairs of DNA, even 100,000 base pairs can provide information about a person's ancestry, according to Moorjani. Many genome analysis programs today only work with nearly complete genome sequences, primarily from recent peoples.

"While ancient DNA is extremely powerful, one of the challenges is that it has much lower quality compared to data from living people because once an individual dies, the DNA begins to degrade, and it's extremely difficult to recover very high-quality data compared to modern individuals," Moorjani explained. "However, the majority of demographic inference methods are designed with the assumption that you can obtain large numbers of samples from populations and high-quality data across the genome." Our methods were created to take advantage of this low-coverage, highly degraded DNA in order to truly understand our evolutionary history."

ASCEND assesses the genetic sharing of individuals within and across populations. When a population is wiped out by a founder event, its size is reduced to a few individuals. These founder individuals' offspring, in turn, share long blocks of DNA that are inherited "identical by descent" from these few ancestors. These blocks will shrink over time as a result of crossover events that occur during meiosis when chromosomes duplicate and mix before segregating into egg and sperm cells. The rate of crossovers is well defined and serves as a molecular clock. The ASCEND program compares the size of shared blocks among individuals in a population to determine when the individuals evolved from a common ancestor, i.e., when a founder event occurred in the population's history. A large-scale, pair-wise statistically significant correlation of genomic DNA enables estimation of when and how severe the bottleneck was.

The genome data comes from the Allen Old DNA Resource, a database created by David Reich and colleagues at Harvard University, where Moorjani received her Ph.D. The public database currently contains more than 14,000 available modern and ancient genomes, as well as over a million common mutations or variants — single nucleotide polymorphisms, or SNPs — within those DNA sequences. When Moorjani began her research, the database contained fewer ancient and modern genomes. She and Tournebize focused on the genomes of 2,310 modern people from 184 groups, then expanded their research to include 1,947 people from 164 worldwide ancient populations.

"Using this method, we discovered previously unknown founder events, such as in ancient Moroccan or Siberian populations," Tournebize said. "As a Frenchman, I was surprised to learn about a founder event in the Basque people, which occurred around the first century BCE and was possibly related to Roman colonization of this region." More genetic data, particularly from ancient samples, as well as collaboration with social scientists, will be required to understand the detailed historical events that may be associated with this bottleneck."

Moorjani and Tournebize chose dogs to check the ASCEND program in other species. The researchers ran the genome sequences of about 40 modern dog breeds through the program to determine how long ago founder events occurred in breeds ranging from African village dogs, which are the least inbred, to breeds like boxers, Dobermans, and rottweilers, which are the most inbred. They confirmed extreme founder events in most breeds within the last 25 generations, or 75 to 125 years, which is consistent with the establishment of many dog breeds during Victorian times.

"It was exciting to expand the analysis to another species because dogs are so interesting," she said. "However, it was really sad to see how strong the founder events are." "Most dogs nowadays have far more issues than village dogs." Their cancer and congenital disease rates are quite high. And this is largely due to the very severe founder events that occurred during breed formation in their history."

Population mixing

Moorjani and her colleagues described a different genomics analysis program in another recent paper that analyzes a single individual's genome, whether complete or partial, and estimates the amount of admixture of other populations over time. The program, called DATES (Distribution of Ancestry Tracts of Evolutionary Signals), was used by the researchers to analyze about 1,100 ancient genomes and reconstruct major gene flow events in Europe since around 10,000 BCE.

The genomes of Anatolian farmers who lived in what is now Turkey show an admixture of genes from Iranian Neolithic farmers long before the advent of agriculture in Anatolia. This implies that farming did not begin in Anatolia, as many archeologists have claimed.

"We had samples of Anatolian hunter-gatherers who did not have Iranian ancestry and samples of Anatolian early farmers who did have Iranian ancestry," she explained. "In our case, we were able to determine the critical time period when this group formed, which predates agriculture in the region." Based on this, we can conclude that farming did not originate in Anatolia but rather spread through cultural diffusion."

Another breakthrough was the timing of the emergence of Bronze Age steppe pastoralists. These groups had a large impact on Eurasia during the Bronze Age, both genetically and demographically, and are thought to be responsible for the spread of Indo-European languages. Archeological studies indicate that these groups lived in steppe regions of modern-day Russia and Ukraine between 3,300 and 2,600 BCE. The researchers discovered these groups were genetically formed between 4,400 and 4,000 BCE, predating previous findings by over a millennium.

"Our study emphasizes the power of dating population mixtures and formation, rather than just using temporal sampling and tracking the presence or absence of a particular ancestry in ancient samples, which is highly dependent on sampling choice and density," said Manjusha Chintalapati, the paper's first author.

Moorjani intends to use ASCEND and DATES to investigate many ancient populations, particularly those in India, that have strong founder events, implying the possibility of many unrecognized recessive diseases that could help to reduce disease burden in the group and shed light on the basic functions of human genes.

"In our analysis, we find that 64 percent of South Asian populations have very strong founder events," she explained. "We are trying to do targeted sample collection in these groups to characterize some of the deleterious variants due to the founder events."

According to DATES, each isolated population in South Asia has admixtures of local indigenous hunter-gatherers, Near Eastern farmers, and Steppe pastoralists or herders, but in different proportions that have remained constant for hundreds of generations. Surprisingly, most European populations have ancestors from the same three groups, though the groups have continued to mix freely after the initial mixture.

"It's really exciting to do this work at Berkeley, where Allan Wilson's lab invented the molecular clock, and to continue on his path of using genomic data to learn about the timing of different evolutionary events," Moorjani said, referring to the late biochemist and molecular evolution pioneer, who died in 1991.

The Burroughs Wellcome Fund, a Sloan Research Fellowship, and the National Institutes of Health-funded the two studies (R35GM142978).

Reference: JOURNAL PLoS Genetics DOI 10.1371/journal.pgen.1010243


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