News Round-Up: May 2010. Neanderthal Special (Updated September 2011)

Neanderthal Man

In the news this week there have been two landmark papers on the sequencing of the Neanderthal* Genome. The results have perhaps been slightly underplayed in the media. If these results are correct, they would have staggering implications for human identity, culture, evolutionary psychology and psychiatry as well as understanding of a number of illnesses. The study of Neanderthals is outside of my field of expertise although a number of findings in the study may have implications for theoretical aspects of psychiatry including specific illnesses although this will require further investigation. This article is a work in progress and will be updated in due course.

The paper was published in Science. The main resources are here:-

  • First paper. A Draft Sequence of the Neandertal Genome is here.
  • Second paper. Targeted Investigation of the Neandertal Genome by Array-Based Sequence Capture is here.
  • Special feature report at Science magazine is here.
  • Science podcast featuring a report on the study here.

The supplementary material can be found here.

Who Were the Neanderthals?

The Neanderthals are considered to be a separate species of Homo Sapiens that diverged from our ancestors in Africa approximately 400,000 years ago. Over the next several hundred thousand years they colonised many other parts of the world – Europe, the Middle East and West Asia. The first officially recognised specimen was obtained from the Neander Valley in Germany although several specimens had previously been discovered elsewhere without an understanding of their significance. They were shorter than modern humans but had a larger cranial capacity on average.

Using reconstructive methods, it has been determined that they were likely very muscular, adapted to moving over short rather than long distances and predominantly carnivorous with the remains of various animal species being found at their sites. It is thought that in Europe, the Neanderthal was well adapted to the cold. Thus for instance it has been suggested that a wider, flatter nose with associated features were useful for heating up cold inhaled air during periods of activity although this has been contested (see this paper). They dominated in the Ice Age of Europe until the arrival of Homo Sapiens Sapiens – our direct ancestors. Then approximately 30,000 years ago they disappeared altogether. For the beginner there is a useful overview of Neanderthals at Wikipedia and there are other useful resources in the Appendix at the bottom fo the page.

What did the Researchers do in their Study ?


The researchers undertook a remarkable piece of research. The methodology section is described at the Science website here. Essentially they took 3 Neanderthal bones from a site in Croatia. These 3 bones varied in age from an estimated 38,000 years before present through to 44,500 years before present. They removed material from the bones with the intention of sequencing the genetic material contained in the bone.

What Problems Did They Encounter?


Much of the biological material they obtained consisted of contaminants – some of it human but much of it bacterial.

How Did They Overcome These Problems?


  • The researchers used a clean room to prepare the material.
  • They used enzymes which preferentially degrade microbial DNA.
  • They also used tags (effectively labels) that bind to ancient DNA to separate this out from other material.

How Did They Sequence the Material?


In the first phase of their analysis the researchers used pyrosequencing. Using this method, the researchers will take a single strand of DNA. They will then build the complementary strand using an enzyme called a DNA polymerase. There are only four building blocks for DNA – which are referred to as A, T, C and G. The building happens one base at a time. So the building enzyme is attached to the Neanderthal DNA single strand and for example the A is presented to it. If the A is the right complementary base then the reaction will take place and light will be generated (because of the material that is being used for the research). This signal will allow the base sequence to be determined. An hypothetical example is describe below

1. The first base in the Neanderthal Genome sequence is A. A only binds with T.

2. The DNA polymerase binds to the single sequence.

3. The DNA polymerase is presented with 4 complementary bases in sequence.

4. Firstly (for example) it is presented with the base A. Nothing happens because A does not bind A.

5. Then it is presented with T.

6. Now the binding takes place because A and T are complementary.

7. A light signal is generated.

8. Using both the light and the presentation of T, it can be deduced that the original base must be A.

9. The sequencing then moves onto the next base.

However, this must take place a single base at a time and cannot continue throughout the entire genome. The genome is very large and they will end up with lots of sequences.

How Did They Combine the Sequences?


The researchers needed a map to help them fit the small sequences together. Imagine it is a bit like a jigsaw puzzle with thousands of pieces but without having an idea of the picture the jigsaw pieces should be forming.

Fortunately, the researchers did have a picture or map to follow. They used the completed Human and Chimpanzee sequences to work out where the smaller sequences should go. They used this in conjunction with algorithms or processes for putting sequences together. The only difficulty is that this gives a low resolution view of the genome but it enabled them to compare the Neanderthal and modern human genomes.

Which Human Genomes did the Researchers Compare the Neanderthal Genome with?


The researchers compared the Neanderthal genome with 5 modern day genomes. People from five regions were selected – Southern Africa (San), Western Africa (Yoruba), China (Han), Western Europe and Papua New Guinea. Since humans and Neanderthals diverged some 400,000 years ago, the researchers expected that all of the human genomes would be quite different from the Neanderthal genome and more similar to each other.

What Did They Find?


  • The researchers were surprised to find that the Neanderthal genome was more similar to the non-African genomes than the African genomes.
  • The researchers used modelling to estimate that between 1 and 4% of the genome of people from Eurasia was contributed to by Neanderthal
  • They also identified a number of regions which Neanderthals shared with Chimpanzees but not humans. These regions contained coding regions for functions including ‘metabolism and cognitive and cranial development’.

Are These Findings Robust?


There are several reasons why these findings might be revised at a later date.

  • The researchers have thus far sequenced 60% of the Neanderthal genome.
  • The process of sequencing will be repeated multiple times to increase the reliability of the results.
  • Laurence Excoffier has suggested here that the comparison data could also be accounted for by Neanderthal and Eurasian Ancestors being separated from the African populations. This would have allowed them to have similar genomes without subsequently interbreeding. This hypothesis needs to be tested.

How Did the Researchers Get a Higher Resolution View of the Genome?


The researchers used another sequencing approach referred to as a micro-array. The principle here is that they used known sequences that are usually bound to a surface. These sequences are known as probes. When they are ‘washed’ with the genetic material under investigation, the material will bind to the probes. The strength with which it binds, is dependent on the base sequences in the genetic material. If it complements a probe, then there will be a strong signal. If there are a few base pairs that are different, the signal will be weaker. Thus identifying the strength of the signals for different probes will show how closely the genetic material in the sample matches. Since the researchers know what the probes are, they will also be able to determine the structure of the genetic material in greater detail. The researchers selected some interesting probes.

How Did the Researchers Select the Probes?


The researchers identified protein coding regions that had changed significantly since our divergence from the Chimpanzee concestor (a concestor is a common ancestor that two species share). 14,000 such regions were used! They compared the results in Neanderthals and 50 modern day humans.

What Did They Find?


The researchers found that in humans there were 88 amino acid substitutions that haven’t changed since humans diverged from Neanderthals. These substitutions occurred in proteins with different functions. Here are some examples.

  • A Pancereatic lipase (PNLIP)
  • A Potassium voltage-gated channel (KCNH8)
  • A Melanin receptor (MCHR2)

The implications of these findings are yet to be fully understood.

Positive Selection for Alleles in Humans


The researchers also found a number of versions of genes – alleles that were positively selected for in humans in comparison to the Neanderthal. Examples include

Chromosome 1 – SELENBP1, POGZ, MIR554, RFX5, SNX27, CGN, TUFT1, PI4KB, PSMB4

Chromosome 2 – ZFP36L2, THADA, HOXD11, HOXD8, EVX2, MTX2, HOXD1, HOXD10, HOXD13, HOXD4, HOXD12, HOXD9, MIR10B, HOXD3

Chromosome 3 – KCNAB1

Chromosome 6 – RUNX2, SUPT3H, BACH2

Chromosome 7 – INHBA, RNF148, RNF133, CADPS2

Chromosome 10 – RHOBTB1, NRG3, BICC1

Chromosome 11 – JRKL, CCDC82, MAML2, CLPB, FOLR1, PHOX2A, FOLR2, INPPL1

Chromosome 14 – MIR337, MIR665, DLK1, RTL1, MIR431, MIR493, MEG3, MIR770

Chromosome 21 – DYRK1A

The researchers noted a few genes of particular interest including DYRK1A. Examining DYRK1A in more detail, a quick search using Wolfram Alpha produces the following.

Clicking on the function of the protein leads to the Entrez Gene database with the following results.

As the researchers have noted, this gene is in the region which duplicated in Down Syndrome (Trisomy 21) and which may be involved in brain development. The researchers also make note of other genes above including NG3 which is associated with Schizophrenia and CDSP2 which has been associated with autism. They refer to AUTS2 but I wasn’t able to see this in Table 3. The researchers also have a very interesting story to tell about the possible role of RUNX2.

The suggestion about NRG3 and Schizophrenia is interesting because there has been speculation that Neanderthals did not experience Schizophrenia as their cortex matured much more quickly than humans. This hypothesis was proposed by Dr Lee Seldon (see here). In the same article, psychiatrist Professor Tim Crow is interviewed and believes that the presence of the gene pair protocadherin XY ‘is responsible for the transition to modern homo sapiens’.

Is There Other Evidence of Neanderthal and Human Interbreeding?


This possibility that humans and Neanderthals interbred has been raised on a number of occasions. There are various pieces of evidence supporting this in addition to the current study

  • Evidence of admixture from the general and dental study of the Abrigo do Lagar Velho child.
  • Preliminary analysis of remains at Pestera Muierilor
  • Analysis of satellite region variation in modern humans (see here). Indeed just to quote from the previous news round-up in April 2010 ‘The researchers predicted two time periods during which interbreeding with another species was necessary to account for their findings. These periods were 55,000 years ago for the Eastern Mediterranean and 45,000 years ago for Eastern Asia’. There were however a number of other possibilities for interbreeding

Which Other Species Might Have Interbred with Humans?


Several hominid species were candidates 50,000 years ago. There may also have been a double-hybridisation.

Reconstruction of  the human ancestor Homo Erectus

What are the Wider Implications of this Study? – What Does It Mean to be Human?

If Neanderthals did interbreed with Eurasians, the researchers in the study have suggested that it may have occurred in the Middle East approximately 100,000 years ago and that this could be consistent with the Out of Africa hypothesis. However one key question here is are Neanderthals and Humans separate species? Daniel Lieberman was quoted in this article as saying

I do not think this in any way lessens the evidence that Neanderthals and modern humans were indeed separate species

It will be very interesting to see the full results of the sequencing when they become available. There is no doubt that the research published by this research group contains an enormous amount of data and that the researchers have demonstrated remarkable ingenuity and perseverance in sequencing this ancient DNA. Despite the wide press coverage (see below), the wider implications of this study are perhaps not yet being realised. In addition, the study data is multilayered and without the need to do any further data collection there are at this point many opportunities to make connections and ‘join the dots’. To say that this is a groundbreaking study is an understatement.

* Note: Both the Neanderthal and Neandertal spellings are valid


Appendix 1

Online Newspapers, Blogs and Websites referencing the study

  • BBC – interview with Professor Finlayson.
  • Bristol University – brief article with useful links to research on possible human-neanderthal interbreeding.
  • Christian Science Monitor – discussion including comparison of Neanderthal, chimpanzee and humans.
  • Lawrence Journal.com – brief article with reference to illness.
  • Mind Hacks – brief mention here.
  • Oregon Live.com – brief tongue-in-cheek take on what an early Neanderthal-Human encounter may have been like.
  • The Washington Post – brief article with references to illness.
  • Trueslant.com – comment on Earth’s Children fiction book about human raised by Neanderthals.
  • Wired – brief article which refers to possible skeletal evidence of interbreeding.

Podcasts

Appendix 2 – Other Resources

Acknowledgements

Homo Erectus and Comparison of Human-Neanderthal skulls images from Wikimedia Commons under a Creative Commons License.

Call for Authors: If you are interested in writing an article or series of articles for this blog please write to the e-mail address below. Copyright can be retained. Index: An index of the site can be found here. The page contains links to all of the articles in the blog in chronological order. Twitter: You can follow ‘The Amazing World of Psychiatry’ Twitter by clicking on this link. Podcast: You can listen to this post on Odiogo by clicking on this link (there may be a small delay between publishing of the blog article and the availability of the podcast). It is available for a limited period. TAWOP Channel: You can follow the TAWOP Channel on YouTube by clicking on this link. Responses: If you have any comments, you can leave them below or alternatively e-mail justinmarley17@yahoo.co.uk. Disclaimer: The comments made here represent the opinions of the author and do not represent the profession or any body/organisation. The comments made here are not meant as a source of medical advice and those seeking medical advice are advised to consult with their own doctor. The author is not responsible for the contents of any external sites that are linked to in this blog.

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