In 1856, a curiously shaped early human skull with cranial features morphologically distinct from modern humans was discovered in Germany. Homo neanderthalensis, commonly known as the Neanderthal, thus became the first human-like species to be known to man. Traditionally, classification of  human-like species has relied on morphological features of fossils, however with the advent of paleogenetics, the study of the past through ancient DNA, we have begun to truly understand the descent of man. With rapid advances in DNA sequencing technology, the field has exploded such that we are learning more than ever about our human evolutionary past. In turn, this is unravelling the mysteries of modern-day human genomes. Reports from the last four years have shown for the first time that our DNA has a lasting archaic legacy, and that our immune system has been shaped by the genetic contributions of our extinct Homo genus family members.

Skull of Homo Neanderthalensis. Image credit: North Carolina School of Science and Mathematics (flickr: NCSSM).
Skull of Homo Neanderthalensis. Image credit: North Carolina School of Science and Mathematics (flickr: NCSSM).

The field of paleogenetics was born in 1984 with the report of the first partial sequences of mitochondrial DNA (mtDNA) from a museum specimen of a quagga, an extinct zebra-like animal. Since then, paleogenetics has been applied to human evolutionary history, ancient pathogens, agricultural history and extinct species. However working with ancient DNA presents several challenges, such as the integrity of sample nucleic acid and contamination from modern sources. DNA begins to decay immediately after death at a rate dictated by its environment, with high temperatures and soil acidity increasinge the rate of decay. For this reason, remains found at higher latitudes and altitudes are ideal for analyzing ancient genetic material. DNA from the Incan Ice Maiden was so well preserved her modern relatives could be accurately identified, whilst DNA extraction has been impossible from the controversial Indonesian “hobbit” Homo floresiensis. In addition, contamination from bacteria and modern humans can also derail a study. For example, DNA sequences cloned from an Egyptian mummy in 1985 were later found to be of modern human origin.

Model of Homo floriensis. Image credit: Karen Neoh (flickr: kneoh)
Model of Homo floresiensis. Image credit: Karen Neoh (flickr: kneoh)

The introduction of high throughput next-generation sequencing (NGS) has given researchers a powerful tool for whole-genome sequencing using ancient DNA. Unknown genomes can be rapidly sequenced from low amounts of genetic material at reasonable costs. This has resulted in a series of revolutionary discoveries in paleogenetics over the last five years, giving us an unprecedented view of our evolutionary history as modern Homo sapiens.

In 2010, using as little as 38,000 year old bones found in a Croatian cave, an international team of researchers reported a low-coverage draft sequence of the Neanderthal genome. Neanderthals are our closet extinct human relative, inhabiting Eurasia from 400,000 to 28,000 years ago. During this time, they coexisted with modern Homo sapiens who had left Africa 60,000 years ago. Whether there was gene flow between previously separated Neanderthals and modern humans, known in the field as admixture, has been hotly debated. Up until 2010, evidence from recovered Neanderthal bones had not indicated such interbreeding. Statistical genome-wide comparisons of Neanderthal genome with genomes from multiple living humans led to the groundbreaking discovery that almost 5% of modern Eurasian genomes, but not African, came from Neanderthals. When applied to existing models of human migration, this suggests that after modern humans left Africa, they interbred with Neanderthals after which the human/Neanderthal hybrid spread across Europe and Asia.

Advances in paleogenetics have also disrupted the long-existing dogma that 40,000 years ago there were only Neanderthals and modern humans living in Eurasia. A finger tip was excavated in Denisova Cave in the Altai mountains of Siberia in 2008, from which a complete mitochondrial DNA sequence and low-coverage genome were sequenced. To the surprise of scientists, comparison with Neanderthal and modern human genomes showed the finger tip bone was from a unique and previously unknown hominin. This was a remarkable first; rather than using morphological evidence, researchers were able to identify a new distinct human-like species based on genomic comparisons. This new hominin was named a “Denisovan” and analysis of its genomic relationships with modern day humans showed that as with Neanderthals, there was evidence of interbreeding with humans.

This discovery has had immediate impacts. It has subsequently been shown that Melanesians, the people who inhabit the south western region of the Pacific Ocean, have inherited up to 6% of their genome from Denisovans. This maps the Denisovans as inhabiting eastern Asia, and suggests that they and the ancestors of Melanesians interbred 40,000 to 60, 000 years ago. Further comparison of archaic genomes with that of living humans will continue to unravel the mysteries of our ancestral human migratory patterns.

From an immunological perspective, perhaps the most fascinating finding from these reports is that admixture between archaic hominins and modern humans has left a lasting legacy on our immune system. In 2011, it was shown that the archaic hominin contribution to Eurasian and Melanesian genomes gave humans functionally advantageous genes. This allowed modern humans to instantly acquire protection from regional diseases and subsequently spread across the planet, overtaking Neanderthals and other hominins.

This was a remarkable first; rather than using morphological evidence, researchers were able to identify a new distinct human-like species based on genomic comparisons.

The human leukocyte antigen (HLA) genes are highly diverse, allowing the collective immune system of a species to overcome diverse pathogenic agents and adapt to new immune challenges. HLA class I genes (HLA-A, -B and –C) are vitally important for immune defense and reproduction and therefore were chosen as probes for admixture. The exceptionally divergent HLA-B allele HLA-B*73:01 is common in modern Eurasians and is concentrated in west Asia, where admixture between modern humans and Neanderthals was proposed to have occurred. It is not present in African populations carrying ancient genetic lineages, supporting the theory that this variant was introduced by admixture in modern humans in west Asia before spreading elsewhere.

Researchers further characterized HLA class I genes from a Denisovan and three Neanderthals. While the Denisovan did not carry B*73, she carried two modern linked HLA-C variants. These two HLA-C variants, HLA-C*15:05 and C*12:02 are in strong linkage disequilibrium with B*73. If modern humans have one of these variants, they will almost always have one of the other two as well. This was circumstantial evidence that B*73 was inherited, along with the other two variants, from interbreeding with Denisovans in Asia.

Other immune system related gene variants from Denisovans and Neanderthals were found in living Eurasians. Ancient human genes encoding unique or strong ligands for natural killer cell receptors, such as the killer-cell immunoglobulin-like receptor (KIR) have been found in non-African modern humans. The researchers argue that this interspecies genetic exchange was driven by its effect on controlling natural killer cells, which are essential for innate immunity, adaptive immunity and placentation. They propose that genes beneficial for immunity and reproduction, when acquired through admixture, spread rapidly through a small but expanding human population. Admixture may have restored diversity after population bottlenecks and helped migrating human pqopulations acquire HLA variants that were adapted to local pathogens.

In early 2014, two groups publishing in Nature and Science presented new methods to identify the archaic genetic legacies in our modern human genomes. Their findings included Neanderthal alleles associated with modern human conditions such as lupus, type 2 diabetes, and Crohn’s disease. The authors suggest that while these genes may not have impacted Neanderthal health, they interacted poorly with modern human DNA. Although acquiring ancient hominid DNA protected modern humans in early life, such an admixture has ultimately made us susceptible to autoimmune disease in later life in a classic example of genetic fitness. Further analysis of archaic genomes may elucidate how the workings of modern human immune systems are influenced by our extinct family members.

A study published January 2014 sequenced the mitochondrial genome of a 400,000 femur from Spain, which represents the oldest archaic hominin sequence to date. The fossil was excavated from a site called Sima de los Huesos (“pit of bones”), and was previously attributed to either early Neanderthals or a common ancestor to Neanderthals and modern humans. Surprising researchers, phylogenetic analysis showed that the femur was more Denisovan than Neanderthal or modern human; Denisovans were proposed to have lived thousands of kilometers away from Spain, and hundreds of thousands years later than Neanderthals. The nuclear genome of this specimen is expected by late 2014, which if successful will demonstrate that DNA can be preserved in a wider range of time and environments then was assumed which will hugely advance the field.

In a field where many hypotheses have been built on small bone fragments and morphological evidence, ancient DNA is playing an unprecedented role in the understanding of human evolutionary processes. Through paleogenetics we are reconstructing history, and by using conscientious approaches to preparing and analyzing ancient DNA, we are re-writing the pages of our story of origin. We are rapidly discovering that the Eurasian Homo family is far more biodiverse than previously hypothesized, and by filling in evolutionary blanks, we are also learning more about ourselves, as exemplified by our archaic immunogenetic legacy.

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Nyrie Israelian

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