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Neanderthal from Chagyrskaya Cave – a High-Coverage Genome
The genome of a Neanderthal from Chagyrskaya Cave in the Altai
Mountains, Russia, was sequenced by Mafessoni et al. (2020) to 27-fold
genomic coverage. It was shown by the results of this study that female
Neanderthal was more closely related to Neanderthals from western
Eurasia Prüfer et al.,
Science 358, 655-658 (2017); Hajdinjak et
al., Nature 555, 652-656
(2018) than to Neanderthals who lived earlier in Denisova Cave [Prüfer
et al., Nature 505, 43-49
(2014), which is located about 100 km from Denisova Cave. Homozygous
regions between 2.5 and 10 centiMorgans (cM) long span about 12.9% of
the Chagyrskaya genome. According to Mafessoni et
al., this is consistent with
the fact that in Siberia Neanderthals lived in populations that were
relatively isolated of 60 individuals. Contrasting with this, a
Neanderthal from Europe, a Denisovan from the Altai Mountains and
ancient modern humans seem to have lived in larger populations. A view
of genetic features that were unique to Neanderthals and that are likely
to have been at high frequency among them has been allowed by the
availability of 3 Neanderthal genomes that were of high quality.
Mafessoni et al. found that
genes that were highly expressed in the striatum in the basal ganglia of
the brain carry more amino acid-changing substitutions than genes that
were expressed elsewhere in the brain, which suggests that in
Neanderthals the striatum may have evolved unique functions.
Evolutionarily, Neanderthals and Denisovans are the closest relatives of
humans of the present. It was shown by analysis of their genomes that
they contributed to people of the present outside sub-Saharan Africa. To
date, however, there are only 2 Neanderthal and 1 Denisovan genomes that
have been sequenced to high quality. Of these Neanderthal genomes
(Vindija 33.19) was recovered from an individual that was found in
Vindija Cave in Croatia (Prüfer et
al., 2014), whereas the other
Neanderthal genome (Denisova 5, or “Altai Neanderthal”) (Green et al.,
2010) and the Denisovan genome (Denisova 3) (Reich et
al., 2010) both are from
specimens that were recovered from Denisova Cave, in the Altai Mountains
in Siberia.
Additional insights into Neanderthal history have been yielded by a
number of archaic genomes of moderate quality (1 to 3-fold genomic
coverage). Genome sequences from 5 late Neanderthals from Europe have
shown that that they carried little genome variation (Mayer et
al., 2012; Prüfer, snpAD) and
were related more closely to the
Vindija 33.19 than to the
Denisova 5 Neanderthal. A genome sequence that was from a bone that
was morphologically undiagnostic from Denisova Cave,
Denisova 11, was from a
direct offspring from a Neanderthal mother and a Denisovan father (Slon
et al., 2018), which
indicated that the 2 groups met in the Altai region. The Neanderthal
mother of Denisova 11 was
related more closely to Vindija
33.19 than to Denisova 5,
which indicates that a replacement of Neanderthal populations in the
Altai Mountains occurred (Slon et
al., 2018).
In this paper Mafessoni et al.
present a high coverage genome sequence of a Neanderthal from
Chagyrskaya Cave that is 106 km west of Denisova Cave (Rudaya et
al., 2017; Kolobova et
al., 2020; Kolobova et
al., 2019; Roberts, Jacob &
Li, 2018). Insights into the population structure and history of
Neanderthals and allows identification of genome features that are
unique to Neanderthals.
Modern day non-African humans carry ~2% (Prüfer et
al., 2016; Hajdinjak, 2018)
Neanderthal ancestry resulting from gene flow from Neanderthals that
took place between 50 and 90 Ka (Prüfer et
al., 2017; Sankararaman et
al., 2012).
Relationship with modern humans
Chagyrskaya
8 shares more alleles, genomewide, non-African humans of the present
than does Denisova 5, a similar proportion of alleles as Vindija 33.19.
If the analysis was restricted to Neanderthal haplotypes that were
detected previously introgressed into humans of the present (Skov et
al., 2018), however, or to
derived alleles that occur at low frequencies in nun-African populations
and that therefore are more likely to be introgressed from Neanderthals,
Vindija 33.19 share more
alleles with populations of the present than does
Chagyrskaya 8.
Vindija 33.19 is related more
closely than Chagyrskaya 8 to
populations of Neanderthals that contributed the majority of DNA to
populations of the present.
In order to test if any populations of modern humans carry an additional
contribution from Neanderthals that are related more closely to
Chagyrskaya 8
than to Vindija 33.19,
Mafessoni et al. used
haplotypes that had been published previously that were inferred to come
from Neanderthals that are presently found exclusively in East Asia,
Europe, India or Oceania. Among 300 genomes from the Simons Genome
Diversity Panel (Mallick et al.,
2016) and 89 Papuan genomes (Vernot et
al., 2016; Malaspinas et
al., 2016), the proportions
of alleles that were shared with
Chagyrskaya 8 and with
Vindija 33.19 contributed to the populations that were tested.
Therefore they concluded that within the limits of the resolution of
these analyses populations of Neanderthals contributed to the genomes of
different populations of modern humans in different proportions (Vernot
& Akey, 2015; Villanea & Schraiber, 2019), these Neanderthal populations
were similarly related to Chagyrskaya 8 and
Vindija.
Small population size and inbreeding
Denisova
5, the Neanderthal genome that was recovered from Denisova Cave, carries
a high proportion of long tracts that are homozygous by descent (HBD
tracts) (Green et al., 2010).
Tracts between 2.5 cM and 10 cM indicate that the population from which
Denisova 5 comes was of small
size over ~100 generations before the individual lived (S1 Appendix 8),
whereas tracts that are more than 10 cM long indicate that the parents
of Denisova 5 were closely
related.
The Chagyrskaya 8 genome
carries fewer HBD tacts that are longer than 10 cM compared to
Denisova 5, but more HBD
tracts of intermediate length (SI Appendix 8). In fact, all 3
high-coverage genomes of Neanderthals that are available carry more HBD
tracts of intermediate size than almost all present day and prehistoric
modern human genomes, as well as the Denisovan genome (Denisova
3). It has been shown by Mafessoni et
al. by coalescent simulations
that this cannot be explained by an overall small though panmictic
population. It suggests, rather, the populations of Neanderthals were
subdivided (SI Appendix 8). They infer by coalescent modelling that
Chagyrskaya 8 and
Denisova 5 may have lived in
subpopulations of 60 or fewer individuals. Contrasting with this,
current and past modern human populations as well as Denisovans (Based
on the genome of Denisova 3)
lived in subpopulations of more than 100 individuals, if it is assumed
there was a migration rate between populations of 1% or less. According
to Mafessoni et al. it is
interesting the Vindija 33.19
seems to have lived in a subpopulation of larger size than the 2
Siberian Neanderthals, though this difference is only marginally
statistically significant when the proportion of the genomes that are
covered by all HBD tracts that are longer than 25 cM is considered
(likelihood-ratio test, P =
0.05).
Derived genomic features in Neanderthals
Mafessoni et al. identified,
by the use of the 3 high-coverage Neanderthal genomes, biological
pathways where protein-coding genes showed more derived nonsynonymous
substitutions fixed in the 3 Neanderthals than was expected from the
polymorphic and silent changes. They identified 993 substitutions that
were nonsynonymous among 899 genes, and 2,952 nonsynonymous
substitutions in the 3 Neanderthals. No groups of genes that are
associated with known biological functions or phenotypes (Köhler et
al., 2014) show a higher
ratio of nonsynonymous to synonymous fixed changes relative to the ratio
of nonsynonymous to synonymous polymorphic changes (MacDonald-Kreitman
ratio) (McDonald & Kreitman, 1991), compared to other groups of genes
(family-wise error rate > 0.1) (Prüfer et
al., 2007).
Mafessoni et al. found,
however, that genes that were expressed in the striatum in individuals
that were 12 – 19 yr of age show a higher MacDonald-Kreitman ratio
(1.02, familywise error rate = 0.029) than genes that were expressed in
other regions of the brain and at other ages (0.53-0.83), when they
analysed genes that were expressed preferentially in different regions
of the brain according to the Allen Bain Atlas (Grot, Prüfer, Kelso &
Dannemann, 2016; Hawrylycz et al.,
2012). It may be indicated by this that negative selection in genes that
are expressed in the striatum was relaxed in Neanderthals. Some of the
proteins that are encoded by these genes might have, alternatively, been
the target of positive selection. Also, genes that are expressed in the
prenatal striatum carry more substitutions in their regions that are
untranslated than genes that are expressed elsewhere (familywise error
rate = 0.049) and at other times. Among genes that are expressed in the
striatum, those that carry fixed nonsynonymous changes in Neanderthals
and present more often in genomic regions that carry little or no DNA
that is introgressed from Neanderthals than striatal genes that do not
carry such changes (Fisher’s exact test
P = 0.026). This pattern in
not observed for all genes that carry fixed nonsynonymous substitutions
in Neanderthals (P>0.1),
which suggests that in Neanderthal striatal genes there are some
substitutions might have been negatively selected in modern humans. As
well as in the striatum, genes that are expressed prenatally in the
posterior parietal cortex, in the ventrolateral prefrontal cortex, and
in the primary somatosensory cortex carry more fixed substitutions in
their regulatory regions in Neanderthals than genes that are expressed
in other regions of the brain and at other times.
Mafessoni et al. performed
the Hudson, Kreitman, Aguadé (HKA) test (Hudson, Kreitman and Aguadé,
1987), and the population branch statistic (PBS) (Yi et
al., 2010) in 25-kb sliding
windows across the genome, in a further attempt to detect positive
selection along the Neanderthal lineage. They estimated the probability
of obtaining the observed values of the different statistics by
coalescence simulations, and retained windows that had a false discovery
rate of <5%. They identified a total of 35 separate candidate regions on
the autosomes. Of these candidate regions, they identified by PBS a
region that was 75 kb long on chromosome 5 that overlaps 2 separate
windows that were identified by HKA. This overlap is lower than it would
have been expected to have been by chance (P
value <4 x 10-4 and SI
Appendix 10). The candidate regions that were identified overlap
genes that are involved in neural development (EXOC6B),
immunity, and wound healing (HTN1,
EVPLL) and mitochondrial functions (NSUN3,
TIMM20). They found that for both statistics there was an overlap
with genomic regions that had been identified previously as being
positively selected in modern humans (Peyrégne, Boyle, Dannemann &
Prüfer, 2017) (enrichment test, P
values = 0.010 and 0.056) for HKA and PBS, respectively).
Discussion
Chagyrskaya
8 is related more closely to
Vindija 33.19 and other late Neanderthals in western Eurasia than to
the Denisova 5 Neanderthal
who lived in the Altai Mountains at an earlier time. Therefore
Chagyrskaya 8 is related to
populations of Neanderthals that moved east at some time between 120 and
80 Ka (Peyrégne et al.,
2019). It is interesting that the artefacts that were found at
Chagyrskaya Cave display similarities to artefact assemblages in central
and eastern Europe (Kolobova et
al., 2020), which suggests that Neanderthal populations that moved
from Eurasia to Siberia may have brought their material culture with
them (Kolobova et al., 2020;
Derevianko et al., 2018).
Local populations of Denisovans were encountered by the incoming
Neanderthals, as is shown by
Denisova 11, who had a Denisovan father and a Neanderthal mother who
was related to the population in which the
Chagyrskaya 8 lived.
It is interesting in this regard that
Chagyrskaya 8 and
Denisova 5 lived in smaller
populations than the Vindija
33.19 Neanderthal in Croatia, the Denisovan
Denisova 3 and modern humans
(Sikora et al., 2017). The
Altai region was on the periphery of the geographical distribution of
Neanderthals and it was suggested that this may have been the reason
that the Neanderthals in the Altai region lived in smaller and more
isolated populations and may have been an area where Denisovans may have
been present more continuously. Mafessoni et
al. suggest more detailed
studies of the population history of Denisova Cave will be necessary to
clarify this.
The number of changes that were expressed in the striatum during
adolescence stands out when analysing genetic changes on the Neanderthal
lineage using the 3 Neanderthal genomes. There is a possibility that
these changes accumulated in the Neanderthals as a result of the small
size of their populations, perhaps in combination with a relaxation of
selection on genes expressed in the striatum. Genes that are expressed
in the striatum overlap more frequently than expected in genomic regions
where Neanderthal introgressed fragments in modern genomes are rare. It
is speculated by Mafessoni et al.
that the
striatal genes may carry changes that are Neanderthal-specific
that were disadvantageous when introduced into modern humans. As well as
positive selection for changes in the modern lineage, this may underlie
so-called Neanderthal deserts in genomes of modern human genomes, i.e.,
regions that are depleted in Neanderthal ancestry
(Vernot et al., 2016;
Sankararaman et al., 2014).
According to Mafessoni et al.
it will become possible to explore genes and groups of genes that
carried functionally relevant changes in Neanderthals more
comprehensively as more high-quality Neanderthal genomes become
available. There is currently suggestive evidence that such findings may
be forthcoming. E.g., as well as genes that are expressed in the
striatum, regions that are untranslated and promoters of genes that are
expressed in posteroventral (inferior) parietal cortex, a region of the
brain that has been associated with speech and mathematical cognition
(Wu et al., 2009), carry more
changes in the 3 Neanderthals than would be expected by chance. Also,
among the top phenotypes that are associated with changes in the
regulatory regions in Neanderthals that are abnormalities in parts of
the skeleton where Neanderthal morphology stand out, such as the nasal
bridge and the rib cage (e.g., Weaver, 2009).
Mafessoni, F., et al. (2020). "A high-coverage Neandertal genome from
Chagyrskaya Cave." Proceedings of the National Academy of Sciences
117(26): 15132-15136.
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Author: M.H.Monroe Email: admin@austhrutime.com Sources & Further reading |