Science - USA (2020-09-25)

INSIGHTS | PERSPECTIVES

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Subsequent to these studies, evidence
has accumulated that suggests a much
earlier meeting between H. sapiens and
Neanderthals in which the main gene flow
went in the opposite direction (H. sapiens
to Neanderthals), first based on nuclear
genomes ( 4 ) and later from mitochondrial
data ( 5 ) (see the figure). This event affected
only Neanderthals and not Denisovans. The
gene flow to the nuclear genome was likely
only 3 to 6% ( 6 ). However, all sequenced
Neanderthal mitochondria are much more
similar to the human mitochondrion than
either are to the Denisovan mitochondrion,
suggesting a total replacement of this or-
ganelle and evidence that H. sapiens fe-
males contributed to gene flow. The event
has been difficult to date, but an upper
bound of about 350,000 years ago can be
derived from the genetic divergence of the
mitochondrion and a lower bound of about
150,000 years ago from evidence that this
gene flow event is shared among all se-
quenced Neanderthals.
Until the new study by Petr et al., ar-
chaeologists had only limited Y chromo-
some data from two Neanderthals ( 7 ) and
no information on exchanges of Y chromo-
somes during the early meeting. The main
reason is that the three fully sequenced
Neanderthal individuals ( 8 – 10 ) and the
single fully sequenced Denisovan individ-
ual ( 11 ) all happen to be females; no bones
with a similar quality of noncontaminated
DNA from archaic males were identi-
fied. Thus, Petr et al. used a capture-
based DNA sequencing approach to
enrich for Y chromosome sequences
in less well-preserved bones from
males. They succeeded in getting us-
able Y chromosome sequences from
three male Neanderthals and two
male Denisovans. The results mirror
exactly the findings from the mito-
chondrion study—complete replace-
ment of Neanderthal Y chromosomes
(and no replacement of Denisovan
Y chromosomes) with H. sapiens Y
chromosomes (see the figure). The
molecular dating falls well within
the estimates from the mitochon-
drion and nuclear studies, making it
a parsimonious explanation that all
admixtures are from the same event.
The new study solves important
questions but fosters even more new
ones. It unequivocally shows that
both male and female H. sapiens con-
tributed to gene flow, suggesting that
both H. sapiens and Neanderthal
populations accepted children of
mixed heritage. Researchers do not
yet have genetic evidence from H. sa-
piens bones outside of Africa for the

period in question, but it seems likely that

they will show evidence of Neanderthal

admixture. There are no genetic traces of

the H. sapiens population from the meet-

ing 350,000 to 150,000 years ago in pres-

ent day humans except for small pieces

of the genome that H. sapiens eventually

got back from Neanderthals in the much

later meeting.

A rapid and total replacement of both

the Y chromosome and mitochondrion

seems too much of a coincidence to be

driven by chance alone, especially given

the relatively small contribution of H. sa-

piens to the Neanderthal nuclear genome.

Some form of natural selection must have

contributed. It is as yet anyone’s guess

what the selective agent might have been.

Because both the Y chromosome and mi-

tochondrion are inherited as nonrecom-

bining units, it is exceedingly difficult to

locate targets of natural selection on them.

GENOME COMPONENT REPLACEMENT (%)

Mitochondrial DNA 100

Y chromosome 100

X chromosome 4–8

Autosomes 3–6

GENOME COMPONENT REPLACEMENT (%)

Mitochondrial DNA 0

Y chromosome 0

X chromosome 


Autosomes 1.5–2

Neanderthals

Neanderthals

Homo sapiens

Homo sapiens

Gene fow from Homo sapiens to Neanderthals (200 to 300 ka ago)

Gene fow from Neanderthals to Homo sapiens (40 to 80 ka ago)

People transfer Gene transfer

Neanderthals likely had a much lower

population size than H. sapiens during

the 500,000 to 700,000 years of separa-

tion ( 9 ), making Neanderthals more prone

to the accumulation of harmful genetic

variants. Petr et al. use simulations of ac-

cumulations of deleterious variants on the

Neanderthal Y chromosome that cause it

to have a lower fitness than the H. sapi-

ens Y chromosome. The results show that

under reasonable parameter assumptions,

this process could explain the replace-

ment; but the authors emphasize that this

is a possibility and not proof. By the same

argument, scientists could expect selection

for the H. sapiens fragments in the nuclear

genome. However, this is not suggested

from the low percentage of H. sapiens frag-

ments in the Neanderthal nuclear genome.

Thus, other selective forces private to the

Y chromosome might be at play. Recent

results suggest complex replacements of

modern human Y chromosomes after the

last out-of-Africa event, which are indica-

tive of recurrent positive selection by an

unknown agent ( 12 ). Y chromosomes have

very fast and structurally complex evolu-

tion ( 13 ), and their variation is associated

strongly with male fertility. The introgres-

sion patterns of X, the Y chromosome part-

ner, also differs notably between the two

gene flow events, with Neanderthal accept-

ing more H. sapiens X chromosomes in the

early meeting and vice versa in the later

meeting. This is the same qualitative

pattern seen for the Y chromosome.

Thus, another possibility is that the

X and Y chromosomes of H. sapiens

and Neanderthals did not fit well to-

gether during male meiosis, and this

affected male fertility. Sequencing

of male Neanderthal bones from

the critical period between 150,000

and 300,000 years ago might resolve

these questions. j

REFERENCES AND NOTES

1. M. Petr et al., Science 369 , 1653 (2020).


2. S. Sankararaman, S. Mallick, N. Patterson, D.
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3. M. Krings et al., Cell 90 , 19 (1997).


4. M. Kuhlwilm et al., Nature 530 , 429 (2016).


5. C. Posth et al., Nat. Commun. 8 , 16046 (2017).


6. M. J. Hubisz, A. L. Williams, A. Siepel, PLOS
   Genet. 16 , e1008895 (2020).


7. M. Hajdinjak et al., Nature 555 , 652 (2018).


8. F. Mafessoni et al., Proc. Natl. Acad. Sci. U.S.A.
   117 , 15132 (2020).


9. K. Prüfer et al., Science 358 , 655 (2017).


10. K. Prüfer et al., Nature 505 , 43 (2014).


11. M. Meyer et al., Science 338 , 222 (2012).


12. P. Hallast et al., Hum. Genet. 10.1007/s00439-
    020-02204-9 (2020).


13. L. Skov, H. Schierup; Danish Pan Genome
    Consortium, PLOS Genet. 13 , e1006834
    (2017).

10.1126/science.abe2766

“...both male and female

H. sapiens contributed to

gene flow, suggesting that both

H. sapiens and Neanderthal

populations accepted children

of mixed heritage.”

1566 25 SEPTEMBER 2020 • VOL 369 ISSUE 6511

Gene flow in two meetings

(Top) A small group of Homo sapiens left Africa for Europe (red arrow),

where they transferred genes to Neanderthals (blue arrow) and

later went extinct. (Bottom) A second, larger group of Homo sapiens

left Africa for Europe (thick red arrow), where they received genes

from Neanderthals who later went extinct (blue arrow, flow in opposite

direction). The tables show the amount of each type of genetic

material transferred after the two migrations. ka, thousand years.