In the middle of the last decade
advances in DNA technology allowed scientists to sequence the genome of the
Chimpanzee (1). The door was thus open to compare the human genome and that of
our nearest relative. The aim was to identify what changes have led to
humanity's unique abilities. Of particular interest were our cognitive
abilities, speech and language and upright mode of locomotion.
A major step towards this goal
was achieved when Pollard publish a pair of papers in 2006 (2 and 3).
In the first paper Pollard (2)
and her co-authors said the following:
“Recent sequencing and assembly of the genome of the common chimp (Pan
troglodytes) offers an unprecedented opportunity to understand primate
evolution and to identify those changes in the ancestral hominoid genome which
gave rise to the modern human species [1]. Primate genome comparisons are
expected to shed light on questions as diverse as the origins of speech [2,3]
and the progression of HIV infection to AIDS [4]. Whereas the aim of
comparative studies of human and rodent genomes [5,6] is typically to identify
genomic elements that are evolutionarily conserved (and therefore presumably
functionally important given the ~150 million years of evolution separating the
species), we look to the chimpanzee genome to better understand what is
uniquely human about our genome. One goal is to find DNA elements that show
evidence of rapid evolution in the human lineage, where “accelerated” or “rapid”
refers to a general increase in the rate of nucleotide substitution. Pollard et
al. [7] used comparative genomics to identify 49 such human accelerated regions
(HARs) that are evolving very slowly in vertebrates but have changed
significantly in the human lineage. The most accelerated of these, HAR1, was
found to be a novel RNA gene expressed during neocortical development [7]. In
this paper, we investigate the properties of a larger set of 202 carefully
screened HARs in order to unravel the evolutionary forces at work behind the
fastest evolving regions of the human genome.
To address questions of human-specific molecular evolution it is not
sufficient to simply identify all nucleotide differences between the human and
chimpanzee genomes. Despite being a small fraction of the human genome, the
number of human bases that differ from the corresponding chimp base is still
large (nearly 29 million bases), and it is likely that most of these
differences do not have a functional consequence. Furthermore, many authors,
starting with the seminal work of King and Wilson [8], have suggested that the
majority of the changes that distinguish humans from other hominoids will be
found in the 98.5% of the genome that is non-coding DNA, which is a vast
territory to search. To identify changes that may be functional, we focus on
the set of regions of the human genome of at least 100 base pairs (bp) that
appear to have been under strong negative selection up to the common ancestor
of human and chimp (as evidenced by high sequence identity between chimp and
rodents), but exhibit a cluster of changes in human compared to chimp. Our
expectation is that the selective constraint on the most extremely accelerated
regions of the human genome may have switched from negative to positive (and possibly
back to negative) some time in the last 5−6 million years.”
Note To allow the reader
to fully appreciate Pollard et. al’s argument I have included the ‘nested’
references from the above under a sub-heading “Pollard 2 references” in my references
section at the end of this post, my own reference appear in round (n) brackets.
Put simply what Pollard et. al.
were saying was:
·
In placental mammals certain genomic areas have
been conserved over a vast stretch of time - 150 million years.
·
The most likely reason for long period of
conservation is that they are “functionally important”.
Yong (9)
neatly describes functionally important DNA thus: “For years, we’ve known that only 1.5 percent of the genome actually
contains instructions for making proteins, the molecular workhorses of our
cells. But ENCODE has shown that the rest of the genome – the non-coding
majority – is still rife with “functional elements”. That is, it’s doing something.
It contains docking sites where proteins can
stick and switch genes on or off. Or it is read and ‘transcribed’ into
molecules of RNA. Or it controls whether nearby genes are transcribed
(promoters; more than 70,000 of these). Or it influences the activity of other
genes, sometimes across great distances (enhancers; more than 400,000 of
these). Or it affects how DNA is folded and packaged. Something.”
·
The authors compared the conserved areas of the
Chimp and human DNA to look for areas of rapid evolution these they named “human
accelerated regions” (HARs).
·
They found 202 such HAR regions of DNA.
·
To identify functional changes in the human
genome as compared to that of the Chimp the authors focus on these HARs.
The paper’s results show the
following
·
The
normalized human substitution rate exceeds the rate in the chimp-rodent
phylogeny in all of the HARs.
·
The divergence
between the human and chimpanzee genomes is higher in the top 49 HARs
·
Directly
comparing substitution rates per site in the human and chimp branches (over the
same period of evolutionary time), the human rate is an average of seven times
higher than the chimp rate in HAR1–HAR5.
·
The
HAR elements themselves are significantly more diverged from chimpanzee than
surrounding sequences
·
The
index of dispersion (i.e., the ratio of the variance in the number of
substitutions on a lineage to the mean number).. in HAR1–HAR5 is much larger
than the expected value of 1.. and
therefore these data are compatible with strong selection on the human
lineage.
·
All
of the observed human-specific changes in HAR1–HAR5 occurred after human
diverged from chimp.
·
These
findings are in agreement with the hypothesis, first proposed by King and
Wilson in 1975, that the majority of chimp-human phenotypic differences can be
explained by differential control of transcriptional networks [8] which may be
expected to occur primarily in the non-coding DNA and in particular in the HAR regions identified (own italics).
In her second paper of 2006
Pollard et. al. looked more closely at the top ranked region of significant
evolutionary acceleration. They reported that the most dramatic of these ‘human
accelerated regions’, HAR1 "is part of a novel RNA gene (HAR1F) that is
expressed specifically in Cajal–Retzius neurons in the developing human
neocortex from 7 to 19 gestational weeks, a crucial period for cortical neuron
specification and migration. HAR1F is co-expressed with reelin, a product of
Cajal–Retzius neurons that is of fundamental importance in specifying the
six-layer structure of the human cortex".
In other words the change in the HAR1 region
is more than like responsible for humanity's differences with respect to higher
functions such as sensory perception, generation of motor commands, spatial
reasoning, conscious thought, and language.
The impact of these two papers
was immense. The identification of the HAR regions opened the door for
researchers to investigate the differences between our nearest hominid relative
the Chimpanzee and answer the question what TRULY makes us human.
This is all well and good, but
HOW did Pollard et. al. accomplish this? Her popular science piece of 2012 for
Scientific American (4) explains the process of hunting for the differences
between the Chimp and Human genomes:
“To facilitate the hunt, I wrote a computer program that would scan the
human genome for the pieces of DNA that have changed the most since humans and
chimps split from a common ancestor. Because most random genetic mutations
neither benefit nor harm an organism, they accumulate at a steady rate that
reflects the amount of time that has passed since two living species had a
common forebear (this rate of change is often spoken of as the “ticking of the
molecular clock”). Acceleration in that rate of change in some part of the
genome, in contrast, is a hallmark of positive selection, in which mutations
that help an organism survive and reproduce are more likely to be passed on to
future generations. In other words, those parts of the code that have undergone
the most modification since the chimp-human split are the sequences that most
likely shaped humankind.
In November 2004, after months of debugging and optimizing my program
to run on a massive computer cluster at the University of California, Santa
Cruz, I finally ended up with a file that contained a ranked list of these
rapidly evolving sequences.”
Pollard further explains what she
did next:
“We spent the next year finding out all we could about the evolutionary
history of HAR1 by comparing this region of the genome in various species,
including 12 more vertebrates that were sequenced during that time. It turns
out that until humans came along, HAR1 evolved extremely slowly. In chickens
and chimps—whose lineages diverged some 300 million years ago—only two of the
118 bases differ, compared with 18 differences between humans and chimps, whose
lineages diverged far more recently. The fact that HAR1 was essentially frozen
in time through hundreds of millions of years indicates that it does something
very important; that it then underwent abrupt revision in humans suggests that
this function was significantly modified in our lineage.”
The result was the two papers
outline above. A nice illustration accompanies her earlier 2009 piece (5) also
in scientific American.
Photo credit: Pollard (5)
Since then a huge amount of research has gone into looking at the HARs.
In 2012 Pollard, herself (4) summarised these:
“HAR1 resides in two
overlapping genes. The shared HAR1 sequence gives rise to an entirely new type
of RNA structure, adding to the six known classes of RNA genes. These six major
groups encompass more than 1,000 different families of RNA genes, each one
distinguished by the structure and function of the encoded RNA in the cell... HAR1
is also the first documented example of an RNA-encoding sequence that appears
to have undergone positive selection..”
“So, too, is the FOXP2 gene,
which contains another of the fast-changing sequences I identified and is known
to be involved in speech. ..FOXP2 extracted
from a Neandertal fossil and found that these extinct humans had the modern
human version of the gene, perhaps permitting them to enunciate as we do.”
“.. human brain volume has more than tripled since the chimp-human
ancestor—a growth spurt that genetics researchers have only begun to unravel.
One of the best-studied examples of a gene linked to brain size in humans and other animals is ASPM. Genetic studies of people with a condition known as microcephaly, in which the brain is reduced by up to 70 percent, uncovered the role of ASPM and another gene—CDK5RAP2—in controlling brain size. More recently, researchers at the University of Chicago, the University of Michigan and the University of Cambridge have shown that ASPM experienced several bursts of change over the course of primate evolution, a pattern indicative of positive selection. At least one of these bursts occurred in the human lineage since it diverged from that of chimps and thus was potentially instrumental in the evolution of our large brains.. Amazingly, more than half of the genes located near HARs are involved in brain development and function..”
One of the best-studied examples of a gene linked to brain size in humans and other animals is ASPM. Genetic studies of people with a condition known as microcephaly, in which the brain is reduced by up to 70 percent, uncovered the role of ASPM and another gene—CDK5RAP2—in controlling brain size. More recently, researchers at the University of Chicago, the University of Michigan and the University of Cambridge have shown that ASPM experienced several bursts of change over the course of primate evolution, a pattern indicative of positive selection. At least one of these bursts occurred in the human lineage since it diverged from that of chimps and thus was potentially instrumental in the evolution of our large brains.. Amazingly, more than half of the genes located near HARs are involved in brain development and function..”
A little more detail on HAR1
activity from Carta Anthropology (6):
“Human Accelerated Regions 1 (HAR1) is part of the cis-antisense RNA
gene pair HAR1F and HAR1R, which are expressed in neurons during human
embryonic cortical development and adult brain. HAR1 is conserved in amniotes
as far back as frogs, but 18 base pair substitutions have occurred specifically
in the human lineage leading to a secondary structure change in HAR1F that is
unique to humans. HAR1F co-expresses with reelin, a protein important to the
proper layering of the human cortex, suggesting an important role for HAR1
in human brain development. In addition, HAR1 expression is repressed by
REST, and it has been hypothesized that changes in HAR1 expression may
contribute to Huntington’s disease phenotypes.”
Photo credit: Pollard (5)
Back to Pollard’s 2012 article. Having
pointed out some of the positive effects of the Human Accelerated Regions of
our genome, Pollard notes that there are some negative consequences associated
with HARs:
PtERV1 is a relic retro-virus that plagued ancient chimps, gorillas and humans living in Africa about four million years ago. Its effects can be found on the genes we have inherited from our ancestors.
Researchers reconstructed the
original PtERV1 sequence and re-created this ancient retrovirus. They then
performed experiments to see how well the human and great ape versions of the
TRIM5α gene could restrict the activity of the resurrected PtERV1 virus. Their
results indicate that most likely a single change in human TRIM5α enabled our
ancestors to fight PtERV1 infection more effectively than our primate cousins
could, however these same shifts make it much harder for us to fight HIV. This
finding is helping researchers to understand why HIV infection leads to AIDS in
humans but less frequently does so in nonhuman primates.
In 2014 Pollard also co-authored a review article (7) with Hubisz
on the work carried out on HARs
“Transgenic [gene regulatory]
enhancer assays also enable the activity of a human ncHAR sequence to be
compared to its ortholog from chimpanzee or other mammals. Of 26 ncHAR
enhancers that have been tested using both human and non-human primate
sequences, seven drive human-specific expression patterns in mouse embryos at
day 11.5. The tissues with differential expression are limb (HAR2, 2xHAR114),
eye (HAR25), forebrain (2xHAR142, 2xHAR238), and the midbrain–hindbrain
boundary (2xHAR164, 2xHAR170). The functional implications of these expression
differences remain to be discovered, but it is tempting to speculate that
changes in the development of these tissues could influence human anatomy and
traits such as fine motor skills, spoken language, and cognition.”
In other words non-coding (nc)HARs are implicated in limb, eye, fore, mid and hindbrain development and thus may affect the development of fine motor skills, language and the higher reasoning skills seen in humanity.
“If the 118 base pair sequence that makes
up HAR1 have been so highly conserved over 300 million years with only 2 base
pair substitutions since chickens and chimps diverged, what type of natural
selection process could account for 18 base pair changes in the span of 6
millions years since we split with the chimps. And why haven't we seen examples
of 4, 6, 8 or more base pair variations in any other species? Is it possible
that the only viable genetic variation for the HAR1 sequence would be the
ancestral and the human versions, with nothing in between? If so, what are the
odds that random mutation could be responsible for 18 base pair changes all
occurring at the same time in such a highly conserved piece of DNA code? I
think these questions should be answered by the author!”
Although at the time, a little logic was needed the commenter could have answered his own question with a little thought.. During the estimated six million (too low a number in my opinion) years since our split from our last common ancestor with Chimpanzees, humanity has been through/on a HUGE genetic odyssey. What species led to and/or contributed genes to, humanity among Ardipithecus, Australopithecus, Homo habilis, Homo erectus, Homo ergastor, Homo heidelburgensis and lastly Homo neaderthalensis is still an open question. However since the interbreeding between Neanderthals and humans has been discovered through the sequencing of Neanderthal genomes, much work has been carried out to understand in what species HARs first began to appear. In their review article (7) Hubisz and Pollard give their take on when HARs first appear on the human tree:
“Genomes from archaic hominins and diverse modern humans provide
information about when along the human lineage HAR mutations arose. We analyzed
ncHARs for mutations shared with a Neanderthal [11] and a Denisovan [12] using other primates (100-way alignments;http://genome.ucsc.edu) to polarize differences. We
estimate that 7.1% of human–chimp differences in ncHARs occurred after divergence
from archaic hominins and 2.7% are shared. The post-archaic fraction is similar
to that observed in targeted sequencing of HARs captured from an Iberian
Neanderthal fossil [31•]. Compared to chimp–human differences in
flanking regions and phastCons elements, those in ncHARs are significantly more
likely to be pre-archaic (90% show derived allele only in Neanderthal and
Denisovan; both P <
0.01). Thus, the archaic hominins provide some evidence for a depletion of
accelerated evolution in the past ∼1
million years of human evolution compared to earlier in our lineage.”
(note: nested references in this passage are given below under ‘Hubisz and Pollard references’ below)
Basically my reading of the above
is that 92.9% (100-7.1) of HARs occurred BEFORE the split between the ancestors
of modern humans and archaic species. In other words MOST of our evolution had
occurred way BEFORE we, modern humans, emerged in Africa ca. 200000 years ago..
Whoa! Now there’s something to ponder!
References
1. The Chimpanzee Sequencing and
Analysis Consortium.Chimpanzee Sequencing and Analysis Consortium (2005) Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437: 69–87.
Full article available at
http://www.nature.com/nature/journal/v437/n7055/full/nature04072.html
2. Pollard K.S., Salama S.R., King B., Kern A.D., Dreszer T., Katzman S., Siepel A., Pedersen J.S., Bejerano R., Baertsch R., et al.
Forces shaping the fastest evolving regions in the human genome. PLoS Genet. 2006;2:1599–1611.
Found at http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.0020168#pgen-0020168-b007
3. Pollard K.S., Salama S.R., Lambert N., Lambot M.A., Coppens S., Pedersen J.S., Katzman S., King B., Onodera C., Siepel A., et al. An RNA gene expressed during cortical development evolved rapidly in humans. Nature. 2006a;443:167–172
Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16915236
4. Pollard K.S., 2012. Secrets of Our Success. What makes us different? Scientific American Volume 22, Issue 1s
5. Pollard K.S. What makes us Human? Sci Am. 2009 May; 300(5):44-9.
6. Carta Anthropology. Retrieved from:
http://carta.anthropogeny.org/moca/topics/human-accelerated-region-1-har1
7. Melissa J Hubisz and Katherine S Pollard. Exploring the genesis and functions of Human Accelerated Regions sheds light on their role in human evolution. Current Opinion in Genetics & Development 2014, 29:15–21
Download at http://www.sciencedirect.com/science/article/pii/S0959437X14000781
8. Comments on “What makes us Human”. Retrieved from:
http://www.scientificamerican.com/article/what-makes-us-human/
9. ENCODE: the rough guide to the human genome By Ed Yong 9/5/2012
Found at http://blogs.discovermagazine.com/notrocketscience/2008/06/14/rna-gene-separates-human-brains-from-chimpanzees/
1. Chimpanzee Sequencing and Analysis Consortium (2005) Initial sequence
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Nature 437: 69–87.
2. Enard W, Przeworski M, Fisher S, Lai C, Wiebe V, et al.
(2002) Molecular
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3. Holden C (2004) The origin of speech. Science 303:
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6. Rat Genome Sequencing Project (2004) Genome sequence of
the brown
Norway rat yields insights into mammalian evolution. Nature
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7. Pollard KS, Salama SR, Lambert N, Coppens S, Pedersen JS,
et al. (2006) An
RNA gene expressed during cortical development evolved
rapidly in humans. Nature. E-pub ahead of print 16 August 2006.
8. King MC, Wilson AC (1975) Evolution at two levels in
humans and
chimpanzees. Science 188: 107–116.Hubisz and Pollard references11. K. Prufer, F. Racimo, N. Patterson, F. Jay, S. Sankararaman, S. Sawyer, A. Heinze, G. Renaud, P.H. Sudmant, C. de Filippo, et al. The complete genome sequence of a Neanderthal from the Altai Mountains. Nature, 505 (2014), pp. 43–49
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31. H.A. Burbano, R.E. Green, T. Maricic, C. Lalueza-Fox, M. de la Rasilla, A. Rosas, J. Kelso, K.S. Pollard, M. Lachmann, S. Paabo
Analysis of human accelerated DNA regions using archaic hominin genomes
PLoS ONE, 7 (2012), p. e32877
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