Science,
Journal Year:
2024,
Volume and Issue:
384(6698)
Published: May 23, 2024
Nucleotide
changes
in
gene
regulatory
elements
are
important
determinants
of
neuronal
development
and
diseases.
Using
massively
parallel
reporter
assays
primary
human
cells
from
mid-gestation
cortex
cerebral
organoids,
we
interrogated
the
cis-regulatory
activity
102,767
open
chromatin
regions,
including
thousands
sequences
with
cell
type-specific
accessibility
variants
associated
brain
regulation.
In
cells,
identified
46,802
active
enhancer
164
that
alter
activity.
Activity
was
comparable
organoids
suggesting
provide
an
adequate
model
for
developing
cortex.
deep
learning
decoded
sequence
basis
upstream
regulators
This
work
establishes
a
comprehensive
catalog
functional
development.
Science,
Journal Year:
2023,
Volume and Issue:
380(6643)
Published: April 27, 2023
Conserved
genomic
sequences
disrupted
in
humans
may
underlie
uniquely
human
phenotypic
traits.
We
identified
and
characterized
10,032
human-specific
conserved
deletions
(hCONDELs).
These
short
(average
2.56
base
pairs)
are
enriched
for
brain
functions
across
genetic,
epigenomic,
transcriptomic
datasets.
Using
massively
parallel
reporter
assays
six
cell
types,
we
discovered
800
hCONDELs
conferring
significant
differences
regulatory
activity,
half
of
which
enhance
rather
than
disrupt
function.
highlight
several
with
putative
effects
on
development,
including
Science,
Journal Year:
2024,
Volume and Issue:
384(6698)
Published: May 23, 2024
Single-cell
genomics
is
a
powerful
tool
for
studying
heterogeneous
tissues
such
as
the
brain.
Yet
little
understood
about
how
genetic
variants
influence
cell-level
gene
expression.
Addressing
this,
we
uniformly
processed
single-nuclei,
multiomics
datasets
into
resource
comprising
>2.8
million
nuclei
from
prefrontal
cortex
across
388
individuals.
For
28
cell
types,
assessed
population-level
variation
in
expression
and
chromatin
families
drug
targets.
We
identified
>550,000
type-specific
regulatory
elements
>1.4
single-cell
quantitative
trait
loci,
which
used
to
build
cell-type
cell-to-cell
communication
networks.
These
networks
manifest
cellular
changes
aging
neuropsychiatric
disorders.
further
constructed
an
integrative
model
accurately
imputing
simulating
perturbations;
prioritized
~250
disease-risk
genes
targets
with
associated
types.
Nature Communications,
Journal Year:
2024,
Volume and Issue:
15(1)
Published: Jan. 30, 2024
To
date
only
a
fraction
of
the
genetic
footprint
thyroid
function
has
been
clarified.
We
report
genome-wide
association
study
meta-analysis
in
up
to
271,040
individuals
European
ancestry,
including
reference
range
thyrotropin
(TSH),
free
thyroxine
(FT4),
and
total
triiodothyronine
(T3),
proxies
for
metabolism
(T3/FT4
ratio)
as
well
dichotomized
high
low
TSH
levels.
revealed
259
independent
significant
associations
(61%
novel),
85
FT4
(67%
62
novel
signals
T3
related
traits.
The
loci
explained
14.1%,
6.0%,
9.5%
1.1%
variation
TSH,
FT4,
concentrations,
respectively.
Genetic
correlations
indicate
that
associated
reflect
determined
by
T3,
whereas
represent
hormone
metabolism.
Polygenic
risk
score
Mendelian
randomization
analyses
showed
effects
genetically
on
various
clinical
outcomes,
cardiovascular
factors
diseases,
autoimmune
cancer.
In
conclusion,
our
results
improve
understanding
physiology
highlight
pleiotropic
diseases.
Science,
Journal Year:
2024,
Volume and Issue:
384(6698)
Published: May 23, 2024
Nucleotide
changes
in
gene
regulatory
elements
are
important
determinants
of
neuronal
development
and
diseases.
Using
massively
parallel
reporter
assays
primary
human
cells
from
mid-gestation
cortex
cerebral
organoids,
we
interrogated
the
cis-regulatory
activity
102,767
open
chromatin
regions,
including
thousands
sequences
with
cell
type-specific
accessibility
variants
associated
brain
regulation.
In
cells,
identified
46,802
active
enhancer
164
that
alter
activity.
Activity
was
comparable
organoids
suggesting
provide
an
adequate
model
for
developing
cortex.
deep
learning
decoded
sequence
basis
upstream
regulators
This
work
establishes
a
comprehensive
catalog
functional
development.
