Genomics euphoria: ramblings of a scientist on genetics, genomics and the meaning of life

Reading an Ancient Genome

Recently, a paper appeared in Science magazine describing a multinational effort to sequence the genome of an archaic individual (an 80,000-year-old Denisovan girl). It actually created a fait bit of hype with news snippets abound (e.g. this one) and a nice wired blog post. Much of the hype, I think, was warranted and this study offers a blueprint for how studies are shaped in the age of genomics and whole-genome sequencing. I will first talk about why I think this study tackles an important problem and then move on to the methodology and results.

Following the genetic trail: the tale of the third chimpanzee

Looking back, I think my introduction to human evolution was mainly through an outstanding book written by Jared Diamond, called “The third chimpanzee“. A lot has changed since then (although, I think the book is still very relevant and a very good read). Many more fossils have been discovered around the world, from Lucy (Australopithecus afarensis) dated to about 3 million years ago to Homo heidelbergensis and Homo erectus specimens dated to less half a million years. These at times partial fossils tell a convincing, albeit incomplete, story of human evolution. However, it was the “Neanderthal Genome Project”, reporting the whole-genome sequence of a 38,000 year old sample from the femur of a Neanderthal specimen, that turned a page on studying the genetics of human evolution. DNA is a vast collection of information and comparing these collections between different species portrays a more vivid picture of their evolutionary trajectories with outstanding details. This information goes significantly beyond what we can learn based on the shape of the fossils and their dates and the circumstances of their finding. It is like finding the black box of a fallen plane: rife with key information that truly shapes our understanding of the events. For example, the Neanderthal Genome Project showed that there had been very little if any interbreeding between humans and Neanderthals (1-4%) with insignificant effects on the evolutionary trajectory of the human genome. Our new-found ability to look into the DNA information has enabled us to reconstruct the evolutionary trajectories with unprecedented resolution. Why is this important? Genetically speaking, I think it is based on where we came from that we can learn where we are headed as a species. And we owe this knowledge to recent advances in high-throughput sequencing.


Sequencing old DNA

DNA is one of the key building blocks of life and its use as genetic material stems, in part, from its surprising stability. Nevertheless, DNA is susceptible to erosion and degradation. This degradation results in very poor DNA quality when extraction is attempted on fossils. Another important point is that conventional methods for preparing samples for high-throughput sequencing relies on double stranded DNA, while DNA degradation results in single stranded DNA becoming a significant portion of the population in fossils. Relying on double-stranded DNA methods not only loses this sizable fraction of DNA, but also results in an enrichment of exogenous contaminant DNA from bacteria or even humans. For example, in the Neanderthal genome project, a significant correlation was observed between the length of the fragment and its similarity to modern humans implying that large fragments (which come from higher quality DNA) were in fact from contaminants. This issue is the exact problem that this study has tackled. They have developed a sequencing strategy that involves single stranded DNA rather than double stranded ones. This method would better capture the degraded samples and it is due to this enhancement that they had actually succeeded in producing a rather high-quality sequence of the ancient fossil. They achieved more than 20-fold coverage of the genome on average, meaning that each position in the genome was read 20 times independently which significantly increases the accuracy of the sequence. In comparison the Neanderthal project scored a 1.5-fold coverage of the genome. This surprising jump in quality is a testament to the effectiveness of their proposed method in sequencing fossilized DNA.

Why does it matter?

This level of coverage and accuracy in sequence enables us to make key inferences both about the individual and the population where she came from. While the fossil was really only a partial bone from a finger and a couple of teeth, the researchers have determined the color of her eyes, hair and skin. But more importantly, with such accuracy, we can tell apart the maternal chromosomes (those coming from the mother) from paternal ones (those coming from the father). What can we do with this information? For starters we can determine whether the parents where close relatives or not (which in this case they weren’t). However, while the parents were not closely related, their genome shows portion of significant similarity. This observation implies that the population in which this girl was living, showed very low genetic diversity. This can be due to the population size. Small populations results in an effect called “bottlenecking” in which few individuals shape the markup of the whole population resulting in very low diversity. Another important finding is that Denisovans (which this girl is a member of) split from modern humans around 180,000 years ago.

What else?

We can gain important insights by comparing this ancient genome to those of modern humans in terms of differences. Looking at the two genomes side-by-side, these researchers observe that a significant fraction of these changes affect brain development and function. While this may not be a surprising observation (since we already associate modern humans with higher brain size and function), it underscores the potential role of brain morphology and development in the evolution of our species.

The plethora of information and knowledge that we gain from a single sequenced genome is outstanding. While we should be cautious of generalizing our findings based on a single individual to whole populations across Asia or even the world, there are in fact no other sources where this knowledge can be found. Similar studies can portray a detailed picture of our genomes and its evolution through ages. A low hanging fruit is to use this novel sequencing methodology to sequence other available samples (including the Neanderthal ones).


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