598 11 FEBRUARY 2022 • VOL 375 ISSUE 6581 science.org SCIENCEA
single, broken molar found buried
within a windswept rock shelter in
southeastern France could push back
the first evidence of modern humans
in Europe by nearly 10,000 years.
According to an international
team, the tooth and dozens of stone tools
from the same sedimentary layer belonged
to a member of Homo sapiens who lived
some 54,000 years ago, a time when Ne-
anderthals were thought to have been the
sole occupants of Europe. The findings also
paint a remarkable picture of the intimacy
of modern humans and their Neanderthal
neighbors, suggesting they may have traded
occupancy of the cave several times—once
in as little as a year.
“I found this paper absolutely fascinat-
ing,” says Kristin Krueger, a dental paleo-
anthropologist at Loyola University Chi-
cago. “From what I can tell, this is solid
evidence ... that modern humans made it to
Europe earlier than thought.”
For others, the excitement is tempered
with caution, especially given that the claim
relies chiefly on a single modern human
tooth. “There are several ‘ifs’ here,” says
paleogeneticist Carles Lalueza-Fox of the
University of Barcelona. “To make a stron-
ger case, we should have at least more solid
skeletal or genetic evidence.”
After arising in Africa, modern humans
trekked into the Middle East as early as
180,000 years ago, where they may have
first met and mated with the Neanderthals,
who already lived in Europe and Asia. (To-
day, non-Africans carry the legacy of those
matings, having inherited about 2% of their
DNA from our closest cousins.) But moderns
were late arrivals in Europe, where until
now the earliest evidence of their remains
and artifacts came from Bulgaria’s Bacho
Kiro Cave, dated to about 45,000 years old.A 10,000-year
head start for
modern humans
in Europe?
Tooth and tools suggest
moderns and Neanderthals
took turns in French cave
PALEOANTHROPOLOGYBy Michael PriceNEWS | IN DEPTH
sometimes order genetic tests to look for dan-
gerous known mutations. With SIDS, studies
that sequenced entire exomes—the protein-
coding regions of DNA—implicated certain
rare genetic mutations. But until now, no
whole-exome studies have looked at a large
collection of SUDC cases to find genetic clues.
A registry of SUDC cases set up by Gould
and Devinsky at the NYU Grossman School
of Medicine in 2014 made such a study pos-
sible. Their team sequenced the exomes of
124 “trios,” each made up of parents and a
child who died suddenly and without expla-
nation between the ages of 11 months and
19 years. The researchers searched for mu-
tations in genes previously associated with
cardiac dysfunction or epilepsy. They found
variants in eight genes that they think con-
tributed to 11 of the deaths, they reported in
the Proceedings of the National Academy of
Sciences in December 2021.
In seven of those cases, the mutation was
de novo, meaning neither parent carries
it—a finding that bolsters the case that it
contributed to death. Six of the variants af-
fected genes involved in calcium signaling—
the flow of ions across cellular channels,
which regulates diverse processes, includ-
ing heart contractions and neuron firing.
In a second study, Holm and colleagues
explored 352 cases of death in either infants
or children. They searched for mutations in
294 genes linked to neurologic conditions,
cardiac dysfunction, and conditions that af-
fect metabolism or multiple organ systems.
In the 73 cases where DNA from both par-
ents was available, they also looked across
the exome for de novo variants. “Likely
contributory variants” emerged for 37 of
the deaths, including six of the 32 deaths
in children older than 1 year, the team re-
ported last month in Genetics in Medicine.
Two of these variants were in genes already
associated with rare neurodevelopmental
disorders but not with sudden death, sug-
gesting an unrecognized potential conse-
quence of those disorders. Both studies
identified mutations in SCN1A, a gene
known to be involved in epilepsy.
The proportions of deaths with possible
explanations in the new studies may seem
small, Hefti says, but the approach applied
broadly could provide new information
to dozens of families in the United States
alone. Learning that the potential cause of
a child’s death is a de novo variant could re-
assure parents that they’re unlikely to have
passed a dangerous mutation to their other
children, he says.
In contrast, if a potential genetic cause
is inherited, other family members could
be tested and take preventive steps if
they’re affected, notes Rachel Rabin, a
genetic counselor at NYU Langone. For ex-
ample, if parents or siblings carry a disease-
linked variation of SCN1A, a neurologist can
run tests and may prescribe medication if
seizures are identified, Rabin says.
Despite the potential value of genetic test-
ing in child or infant death investigations,
it’s not always done. “The factors are mostly
money, of course,” says Michael Klintschar,
a forensic pathologist at Hannover Medical
School. Among U.S. medical examiners’ of-
fices, “I would guess that the majority do
not do [genetic testing] on every case,” says
Kathryn Pinneri, director of Montgomery
County Forensic Services in Conroe, Texas,
and president of the National Association of
Medical Examiners. But declining costs have
made it more common in the past 5 years,
she says.
The New York City medical examiner’s of-
fice investigates unexplained deaths among
infants and children using its own panels
of genetic tests. Geneticist Yingying Tang,
who heads the in-house molecular genetics
lab there, says the new study results make
her “pretty confident with the cardiac and
epilepsy panels I have.” Investigations of
pediatric deaths in that office have revealed
mutations in several of the genes identified
in these studies, she says.
Some parents of children who died sud-
denly hope genetic analysis will make it
possible to screen embryos for a dangerous
genetic variant before another pregnancy,
says Richard Goldstein, a palliative care
pediatrician at Boston Children’s and co-
author of the new study. Developing and
justifying such screening would require
first firming up any causal link between a
variant and sudden death. His team plans
to delve into the mechanisms of some of
the recently identified variants by insert-
ing them into zebrafish to look for differ-
ences in behavior or life span.
In principle, some dangerous variants
could be added to those routinely screened
for in newborns, Devinsky says. “I think
that’s where [the field] should probably
go.” But in many cases the consequences
of a mutation remain obscure, Klintschar
notes. Linking a child’s death to a rare
mutation in an arrhythmia-related gene
doesn’t tell researchers the risk of cardiac
arrest in a living baby with the same mu-
tation. Giving all such children implants
to correct irregular rhythms might cause
more problems than it solves, he says.
Gould, whose daughter’s death remains
unexplained, hopes the SUDC registry can
help clarify the risk factors. It now in-
cludes 292 families, and her team contin-
ues to invite parents to participate. “If you
want your child’s information to benefit
research,” she says, “that opportunity can
sometimes be comforting.” j