lunes, 14 de julio de 2014

Researchers probe inner workings of ancient human genomes, compare them to humans

Researchers probe inner workings of ancient human genomes, compare them to humans

Genome.gov National Human Genome Research Institute National Institutes of Health

Ancient and modern man
In the past decade, researchers have made a series of impressive discoveries while reconstructing the genomes of some of our closest, long-extinct relatives. They have extracted ancient DNA from the fossilized bones of both Neanderthals and Denisovans, who split from us about 550,000-750,000 years ago. These two groups of ancient humansappeared different from us, with heavier brows, shorter stature, larger muscles and coarser body hair, and perhaps behaved differently from us, as less social creatures. But at the genomic level, they're over 99 percent the same as we Homo sapiens.

One way to study how these genetic differences may have led to differences in physical and behavioral manifestations, would be to focus on the changes seen in the less-than-1 percent sliver of DNA that separates Homo Sapiens from our ancient ancestors. Another, complimentary approach to untangling these differences would be to study the epigenetic patterns, the chemical code that sits on top of genes and regulates their actions, like a railway switch at a train station. One such part of the epigenetic code is the methylation pattern, which controls genes like a dimmer on a light switch. Higher amounts of DNA methylation (hypermethylation) decrease a gene's activity, while  lower amounts of DNA methylation (hypomethylation) increase a gene's activity. Unfortunately, the epigenetic code is unlike DNA-it's delicate and degrades quickly, whereas DNA may remain intact for millennia.
 
Recent advances in the study of ancient genomes and their patterns of decay now allow scientists to indirectly study parts of the epigenetic code-the methylation patterns-in our ancient forbears so that we can compare it to the patterns seen in present-day humans. May's Genome Advance of the Month describes a study in Science by an international team of researchers that reconstructed parts of the epigenetic code in both Neanderthals and Denisovans.
 
To reconstruct the ancient humans' methylation pattern, the team began by analyzing what was left: the DNA sequence found in bone fragments. They combed through these sequences searching for stretches of DNA that contained a high ratio of two bases, cytosine and thymine, in close proximity. Higher ratios of these Cs and Ts are an indication of epigenetic methylation. This happens for two reasons: First, methyl chemical groups attach to cytosines, and second, when methyl groups are attached to cytosines, the cytosine-methyl groups often degrade into thymines. This is in contrast to unmethylated cytosines, which will generally degrade into uracils. Thus, clusters of many Cs and Ts in the ancient genomes indicated an area where researchers could infer methylation of the DNA.
 
To double-check these inferences, the researchers compared their predicted methylation patterns to known methylation patterns in genes that are shared by both ancient and modern humans, the housekeeping genesthat regulate basic cell functions. Their theoretical (hypomethylated) pattern of the housekeeping genes correlated highly with the actual pattern seen in modern-day humans, and, perhaps more importantly, they found no changes in the methylation patterns between ancient and living humans. Reassured by their findings, the researchers then analyzed the Neanderthal and Denisovan bone cell DNA for areas of methylation, comparing those to the methylation patterns in 37 different bone samples from modern humans.
 
What they found was like déjà vu from previous research on ancient genomes. After analyzing the groups, the researchers found that 99 percent of the methylation patterns were the same between modern-day humans and our extinct relatives. Within the 1 percent that differed between the three groups, the researchers identified roughly 2,000 regions with significantly different methylation patterns. One of these regions was in the HOXD genes, a cluster of five genes that helps regulate limb growth. In present-day humans, the HOXD9 promoter and HOXD10 gene were hypomethylated in all the samples, leading to higher expression, but in the ancient humans these areas were hypermethylated, which could indicate lower levels of expression or outright gene silencing, leading to shorter limbs and stature. The researchers believe these changes may have played a part in the evolution of modern human limbs.
 
Additionally, the team studied differences in methylation of transcription factor proteins (TFs). These proteins influence the expression of other proteins, so a change in the methylation pattern of one TF can have a cascade effect, rippling out across the genome. As expected, there were differences in TF methylation patterns, with present-day humans showing changes in TFs that influence the growth and development of muscles, lymphocytes and neurons, and another TF that interacts with both HOXD9 and HOXD10. The researchers think this might be a clue as to how the changes in TF methylation from ancient humans to modern humans might explain other changes throughout the genome, which they think could lead to "bursts" of evolution.
 
Lastly, the team noted a curious finding: Among present-day humans, almost 20 percent of the genes with different methylation patterns (higher and lower) were found within disease-related genes. The ailments involving these genes range from neurological to psychiatric disorders. Although it might be easy to conclude that these changes could result in higher rates of disease, the researchers cautioned that it remains unclear whether these methylation changes led to the emergence of a disease or if changes are simply more common in these genes.
 
Overall, the researchers found a precise way to indirectly determine the methylation pattern reconstructing this part of the epigenetic code in extinct humans, which would otherwise be lost to time. These patterns elucidate part of the inner workings of the ancient humans' genomes and how they differ from our own. The researchers were quick to point out that differences in the epigenetic pattern don't necessarily explain the physical and behavioral differences between and us and our ancient counterparts. However, these differences may help explain some of the variation between Homo sapiens, Neanderthals and Denisovans, as well as the mechanisms that lead to subtle changes in the structure of their genome. These small changes may have eventually led to changes in behaviors and bodies, leading to our modern forms, and perhaps may help write another page in the story of human evolution.

Read the Study
Gokhman, D., Lavi, E., Prüfer, K., Fraga, M. F., Riancho, J. A., Kelso, J., Pääbo, S., Meshorer, E. Carmel, L. Reconstructing the DNA Methylation Maps of the Neandertal and the Denisovan. Science344(6183), 523-7. 2014. [PubMed]

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