Heart
development
and
rhythm
control
are
highly
Tbx5
dosage-sensitive.
TBX5
haploinsufficiency
causes
congenital
conduction
disorders,
whereas
increased
expression
levels
of
in
human
heart
samples
has
been
associated
with
atrial
fibrillation
(AF).
We
deleted
the
conserved
mouse
orthologues
two
independent
AF-associated
genomic
regions
locus,
one
intronic
(RE(int))
downstream
(RE(down))
.
In
both
lines,
we
observed
a
modest
(30%)
increase
postnatal
atria.
To
gain
insight
into
effects
slight
dosage
vivo,
investigated
transcriptional,
epigenetic
electrophysiological
properties
lines.
Increased
was
induction
genes
involved
development,
ion
transport
conduction,
susceptibility
to
arrhythmias,
action
potential
duration
cardiomyocytes.
identified
an
variant
RE(int)
that
increases
its
transcriptional
activity.
Expression
transcription
factor
Prrx1
induced
RE(int)KO
found
some
functional
changes
atria
caused
by
were
normalized
when
reducing
cardiac
mice,
indicating
interaction
between
these
AF
genes.
conclude
dose-dependent
factors,
common
regulatory
variants,
significantly
impact
on
gene
network
disease
susceptibility.
Cell Genomics,
Год журнала:
2024,
Номер
4(4), С. 100536 - 100536
Опубликована: Апрель 1, 2024
Gene
regulatory
divergence
between
species
can
result
from
cis-acting
local
changes
to
element
DNA
sequences
or
global
trans-acting
the
environment.
Understanding
how
these
mechanisms
drive
evolution
has
been
limited
by
challenges
in
identifying
changes.
We
present
a
comprehensive
approach
directly
identify
cis-
and
trans-divergent
elements
human
rhesus
macaque
lymphoblastoid
cells
using
assay
for
transposase-accessible
chromatin
coupled
self-transcribing
active
region
(ATAC-STARR)
sequencing.
In
addition
thousands
of
cis
changes,
we
discover
an
unexpected
number
(∼10,000)
trans
show
that
exhibit
distinct
patterns
sequence
function.
further
differentially
expressed
transcription
factors
underlie
∼37%
differences
trace
produce
cascades
Overall,
find
most
divergent
(67%)
experienced
both
trans,
revealing
substantial
role
divergence-alone
together
with
changes-in
species.
Neurotherapeutics,
Год журнала:
2024,
Номер
21(1), С. e00316 - e00316
Опубликована: Янв. 1, 2024
Mitochondria
are
critical
for
brain
development
and
homeostasis.
Therefore,
pathogenic
variation
in
the
mitochondrial
or
nuclear
genome
which
disrupts
function
frequently
results
developmental
disorders
neurodegeneration
at
organismal
level.
Large-scale
application
of
genome-wide
technologies
to
individuals
with
diseases
has
dramatically
accelerated
identification
disease-gene
associations
humans.
Multi-omic
high-throughput
studies
involving
transcriptomics,
proteomics,
metabolomics,
saturation
editing
providing
deeper
insights
into
functional
consequence
genomic
variation.
Integration
deep
phenotypic
data
through
allelic
series
continues
uncover
novel
functions
permit
gene
dissection
on
an
unprecedented
scale.
Finally,
illuminate
disease
mechanisms
thereby
direct
therapeutic
strategies
small
molecules
RNA-DNA
therapeutics.
This
review
summarizes
progress
genomics
molecule
therapeutics
neurodevelopmental
disorders.
Bioinformatics,
Год журнала:
2022,
Номер
38(23), С. 5168 - 5174
Опубликована: Окт. 10, 2022
The
advent
of
massive
DNA
sequencing
technologies
is
producing
a
huge
number
human
single-nucleotide
polymorphisms
occurring
in
protein-coding
regions
and
possibly
changing
their
sequences.
Discriminating
harmful
protein
variations
from
neutral
ones
one
the
crucial
challenges
precision
medicine.
Computational
tools
based
on
artificial
intelligence
provide
models
for
sequence
encoding,
bypassing
database
searches
evolutionary
information.
We
leverage
new
encoding
schemes
an
efficient
annotation
variants.
Heart
development
and
rhythm
control
are
highly
Tbx5
dosage-sensitive.
TBX5
haploinsufficiency
causes
congenital
conduction
disorders,
whereas
increased
expression
levels
of
in
human
heart
samples
has
been
associated
with
atrial
fibrillation
(AF).
We
deleted
the
conserved
mouse
orthologues
two
independent
AF-associated
genomic
regions
locus,
one
intronic
(RE(int))
downstream
(RE(down))
.
In
both
lines,
we
observed
a
modest
(30%)
increase
postnatal
atria.
To
gain
insight
into
effects
slight
dosage
vivo,
investigated
transcriptional,
epigenetic
electrophysiological
properties
lines.
Increased
was
induction
genes
involved
development,
ion
transport
conduction,
susceptibility
to
arrhythmias,
action
potential
duration
cardiomyocytes.
identified
an
variant
RE(int)
that
increases
its
transcriptional
activity.
Expression
transcription
factor
Prrx1
induced
RE(int)KO
found
some
functional
changes
atria
caused
by
were
normalized
when
reducing
cardiac
mice,
indicating
interaction
between
these
AF
genes.
conclude
dose-dependent
factors,
common
regulatory
variants,
significantly
impact
on
gene
network
disease
susceptibility.
