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.
Science,
Journal Year:
2023,
Volume and Issue:
380(6643)
Published: April 27, 2023
Zoonomia
is
the
largest
comparative
genomics
resource
for
mammals
produced
to
date.
By
aligning
genomes
240
species,
we
identify
bases
that,
when
mutated,
are
likely
affect
fitness
and
alter
disease
risk.
At
least
332
million
(~10.7%)
in
human
genome
unusually
conserved
across
species
(evolutionarily
constrained)
relative
neutrally
evolving
repeats,
4552
ultraconserved
elements
nearly
perfectly
conserved.
Of
101
significantly
constrained
single
bases,
80%
outside
protein-coding
exons
half
have
no
functional
annotations
Encyclopedia
of
DNA
Elements
(ENCODE)
resource.
Changes
genes
regulatory
associated
with
exceptional
mammalian
traits,
such
as
hibernation,
that
could
inform
therapeutic
development.
Earth's
vast
imperiled
biodiversity
offers
distinctive
power
identifying
genetic
variants
function
organismal
phenotypes.
Science,
Journal Year:
2021,
Volume and Issue:
373(6562), P. 1468 - 1473
Published: Sept. 23, 2021
The
sequencing
of
the
human
genome
has
allowed
study
genetic
architecture
common
diseases:
number
genomic
variants
that
contribute
to
risk
disease
and
their
joint
frequency
effect
size
distribution.
Common
diseases
are
polygenic,
with
many
loci
contributing
phenotype,
cumulative
burden
alleles
determines
individual
in
conjunction
environmental
factors.
Most
occur
noncoding
regions
regulating
cell-
context-specific
gene
expression.
Although
sizes
most
small,
effects
individuals,
quantified
as
a
polygenic
(risk)
score,
can
identify
people
at
increased
disease,
thereby
facilitating
prevention
or
early
intervention.
Science,
Journal Year:
2023,
Volume and Issue:
380(6646)
Published: May 4, 2023
Most
variants
associated
with
complex
traits
and
diseases
identified
by
genome-wide
association
studies
(GWAS)
map
to
noncoding
regions
of
the
genome
unknown
effects.
Using
ancestrally
diverse,
biobank-scale
GWAS
data,
massively
parallel
CRISPR
screens,
single-cell
transcriptomic
proteomic
sequencing,
we
discovered
124
Cell Metabolism,
Journal Year:
2023,
Volume and Issue:
35(4), P. 695 - 710.e6
Published: March 23, 2023
Associations
between
human
genetic
variation
and
clinical
phenotypes
have
become
a
foundation
of
biomedical
research.
Most
repositories
these
data
seek
to
be
disease-agnostic
therefore
lack
disease-focused
views.
The
Type
2
Diabetes
Knowledge
Portal
(T2DKP)
is
public
resource
datasets
genomic
annotations
dedicated
type
diabetes
(T2D)
related
traits.
Here,
we
make
the
T2DKP
more
accessible
prospective
users
useful
existing
users.
First,
evaluate
T2DKP's
comprehensiveness
by
comparing
its
with
those
other
repositories.
Second,
describe
how
researchers
unfamiliar
can
begin
using
correctly
interpreting
them
via
T2DKP.
Third,
extend
their
current
workflows
use
full
suite
tools
offered
We
finally
discuss
lessons
toward
goal
democratizing
access
complex
disease
results.
Science,
Journal Year:
2023,
Volume and Issue:
380(6643)
Published: April 27, 2023
Thousands
of
genomic
regions
have
been
associated
with
heritable
human
diseases,
but
attempts
to
elucidate
biological
mechanisms
are
impeded
by
an
inability
discern
which
positions
functionally
important.
Evolutionary
constraint
is
a
powerful
predictor
function,
agnostic
cell
type
or
disease
mechanism.
Single-base
phyloP
scores
from
240
mammals
identified
3.3%
the
genome
as
significantly
constrained
and
likely
functional.
We
compared
annotation,
association
studies,
copy-number
variation,
clinical
genetics
findings,
cancer
data.
Constrained
enriched
for
variants
that
explain
common
heritability
more
than
other
functional
annotations.
Our
results
improve
variant
annotation
also
highlight
regulatory
landscape
still
needs
be
further
explored
linked
disease.
PROTEOMICS,
Journal Year:
2022,
Volume and Issue:
23(7-8)
Published: Nov. 9, 2022
Abstract
There
are
multiple
reasons
why
the
next
generation
of
biological
and
medical
studies
require
increasing
numbers
samples.
Biological
systems
dynamic,
effect
a
perturbation
depends
on
genetic
background
environment.
As
consequence,
many
conditions
need
to
be
considered
reach
generalizable
conclusions.
Moreover,
human
population
clinical
only
sufficient
statistical
power
if
conducted
at
scale
with
precise
measurement
methods.
Finally,
proteins
remain
without
functional
annotations,
because
they
have
not
been
systematically
studied
under
broad
range
conditions.
In
this
review,
we
discuss
latest
technical
developments
in
mass
spectrometry
(MS)‐based
proteomics
that
facilitate
large‐scale
by
fast
efficient
chromatography,
scanning
spectrometers,
data‐independent
acquisition
(DIA),
new
software.
We
further
highlight
recent
which
demonstrate
how
high‐throughput
(HT)
can
applied
capture
diversity,
annotate
gene
functions
or
generate
predictive
prognostic
models
for
diseases.
Nature,
Journal Year:
2023,
Volume and Issue:
625(7996), P. 735 - 742
Published: Nov. 29, 2023
Abstract
Noncoding
DNA
is
central
to
our
understanding
of
human
gene
regulation
and
complex
diseases
1,2
,
measuring
the
evolutionary
sequence
constraint
can
establish
functional
relevance
putative
regulatory
elements
in
genome
3–9
.
Identifying
genomic
that
have
become
constrained
specifically
primates
has
been
hampered
by
faster
evolution
noncoding
compared
protein-coding
10
relatively
short
timescales
separating
primate
species
11
previously
limited
availability
whole-genome
sequences
12
Here
we
construct
a
alignment
239
species,
representing
nearly
half
all
extant
order.
Using
this
resource,
identified
are
under
selective
across
other
mammals
at
5%
false
discovery
rate.
We
detected
111,318
DNase
I
hypersensitivity
sites
267,410
transcription
factor
binding
but
not
placental
validate
their
cis
-regulatory
effects
on
expression.
These
enriched
for
genetic
variants
affect
expression
traits
diseases.
Our
results
highlight
important
role
recent
differentiating
primates,
including
humans,
from
mammals.
