Spotlight

A showcase of research and scholarship

in selected articles from 2018 in selected articles from 2018
A showcase of research and scholarship

Spotlight
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ON THE COVER Hydrangeas change the color of their blooms in response to soil pH.
Ferdoush et al. demonstrate a metaphorical mimicry of such a phenomenon at the level
of gene activation, where the activator in budding yeast functionally alternates between
coactivators SAGA and NuA4 in response to inorganic phosphate to promote transcription
of a high-affinity inorganic phosphate transporter gene, PHO84.
2 Photo: Arpan Roy. See Ferdoush et al. Genetics 208: 191–205.
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3
 2018 EDITORS’ CHOICE AWARD: MOLECUL AR GENE TICS

Transgenerational Epigenetic Inheritance

Is Negatively Regulated by the HERI-1
Chromodomain Protein
Roberto Perales, Daniel Pagano, Gang Wan, Brandon D. Fields, Arneet L. Saltzman,
and Scott G. Kennedy
Genetics December 2018 210: 1287–1299

EDITORS’ NOTE C. elegans is a well-established model organism for the

investigation of the transgenerational epigenetic inheritance (TEI) mediated
by small RNAs. The mechanisms by which TEI is regulated are not well
understood. Perales et al. identified a negative regulator of TEI expressed in
the germline that is recruited to target genes via the nuclear RNAi machinery.
The authors propose that the generational perdurance of RNAi inheritance is
set by competing outputs of this machinery.

ABSTRACT Transgenerational epigenetic inheritance (TEI) is the inheritance

of epigenetic information for two or more generations. In most cases, TEI is
limited to a small number of generations (two to three). The short-term nature
of TEI could be set by innate biochemical limitations to TEI or by genetically
encoded systems that actively limit TEI. In Caenorhabditis elegans, double-
stranded RNA (dsRNA)-mediated gene silencing [RNAi (RNA interference)]
can be inherited (termed RNAi inheritance or RNA-directed TEI). To identify
systems that might actively limit RNA-directed TEI, we conducted a forward
genetic screen for factors whose mutation enhanced RNAi inheritance. This
screen identified the gene heritable enhancer of RNAi (heri-1), whose mutation
causes RNAi inheritance to last longer (> 20 generations) than normal. heri-1
encodes a protein with a chromodomain, and a kinase homology domain that
is expressed in germ cells and localizes to nuclei. In C. elegans, a nuclear
branch of the RNAi pathway [termed the nuclear RNAi or NRDE (nuclear
RNA defective) pathway] promotes RNAi inheritance. We find that heri-1(–)
animals have defects in spermatogenesis that are suppressible by mutations
in the nuclear RNAi Argonaute (Ago) HRDE-1, suggesting that HERI-1 might
normally act in sperm progenitor cells to limit nuclear RNAi and/or RNAi
inheritance. Consistent with this idea, we find that the NRDE nuclear RNAi
pathway is hyperresponsive to experimental RNAi treatments in heri-1 mutant
animals. Interestingly, HERI-1 binds to genes targeted by RNAi, suggesting
that HERI-1 may have a direct role in limiting nuclear RNAi and, therefore,
RNAi inheritance. Finally, the recruitment of HERI-1 to chromatin depends
upon the same factors that drive cotranscriptional gene silencing, suggesting
that the generational perdurance of RNAi inheritance in C. elegans may be set
by competing pro- and antisilencing outputs of the nuclear RNAi machinery.

4
 2018 EDITORS’ CHOICE AWARD: POPUL ATION GENE TICS

The Evolution of Polymorphic Hybrid

Incompatibilities in House Mice
Erica L. Larson, Dan Vanderpool, Brice A. J. Sarver, Colin Callahan, Sara Keeble,
Lorraine L. Provencio, Michael D. Kessler, Vanessa Stewart, Erin Nordquist, Matthew
D. Dean, and Jeffrey M. Good
Genetics July 2018 209: 845–859

EDITORS’ NOTE Reproductive barriers are often assumed to arise from fixed
genetic differences between species, despite frequent individual variation
in the strength of reproductive isolation between populations. Larson et al.
report polymorphism at several hybrid male sterility loci in house mice, and
their results demonstrate that selection against deleterious hybrid interactions
can drive the introgression of hybrid incompatibilities, highlighting the need for
more extensive sampling of natural variation in speciation studies.

ABSTRACT Resolving the mechanistic and genetic bases of reproductive

barriers between species is essential to understanding the evolutionary
forces that shape speciation. Intrinsic hybrid incompatibilities are often
treated as fixed between species, yet there can be considerable variation
in the strength of reproductive isolation between populations. The extent
and causes of this variation remain poorly understood in most systems.
We investigated the genetic basis of variable hybrid male sterility (HMS)
between two recently diverged subspecies of house mice, Mus musculus
domesticus and Mus musculus musculus. We found that polymorphic HMS
has a surprisingly complex genetic basis, with contributions from at least
five autosomal loci segregating between two closely related wild-derived
strains of M. m. musculus. One of the HMS-linked regions on chromosome
4 also showed extensive introgression among inbred laboratory strains and
transmission ratio distortion (TRD) in hybrid crosses. Using additional crosses
and whole genome sequencing of sperm pools, we showed that TRD was
limited to hybrid crosses and was not due to differences in sperm motility
between M. m. musculus strains. Based on these results, we argue that
TRD likely reflects additional incompatibilities that reduce hybrid embryonic
viability. In some common inbred strains of mice, selection against deleterious
interactions appears to have unexpectedly driven introgression at loci involved
in epistatic hybrid incompatibilities. The highly variable genetic basis to F1
hybrid incompatibilities between closely related mouse lineages argues that a
thorough dissection of reproductive isolation will require much more extensive
sampling of natural variation than has been commonly utilized in mice and
other model systems.

5
 2018 EDITORS’ CHOICE AWARD: QUANTITATIVE GENE TICS

Mutational Pleiotropy and the Strength of

Stabilizing Selection Within and Between
Functional Modules of Gene Expression
Julie M. Collet, Katrina McGuigan, Scott L. Allen, Stephen F. Chenoweth, and
Mark W. Blows
Genetics April 2018 208: 1601–1616

EDITORS’ NOTE Collet et al. adopted a high-dimensional quantitative

genetic approach to test for the presence of modularity of the genotype-
phenotype map. Using gene expression traits, they examined whether
traits contributing to the same function (functional modularity) are more
strongly genetically correlated (variational modularity) than traits belonging
to different functions. They found little evidence that functional modules
predict variational modules; however, they detected large variational modules
spanning several functional modules.

ABSTRACT Variational modules, sets of pleiotropically covarying traits,

affect phenotypic evolution, and therefore are predicted to reflect functional
modules, such that traits within a variational module also share a common
function. Such an alignment of function and pleiotropy is expected to facilitate
adaptation by reducing the deleterious effects of mutations, and by allowing
coordinated evolution of functionally related sets of traits. Here, we adopt a
high-dimensional quantitative genetic approach using a large number of gene
expression traits in Drosophila serrata to test whether functional grouping,
defined by gene ontology (GO terms), predicts variational modules. Mutational
or standing genetic covariance was significantly greater than among randomly
grouped sets of genes for 38% of our functional groups, indicating that
GO terms can predict variational modularity to some extent. We estimated
stabilizing selection acting on mutational covariance to test the prediction that
functional pleiotropy would result in reduced deleterious effects of mutations
within functional modules. Stabilizing selection within functional modules was
weaker than that acting on randomly grouped sets of genes in only 23% of
functional groups, indicating that functional alignment can reduce deleterious
effects of pleiotropic mutation but typically does not. Our analyses also
revealed the presence of variational modules that spanned multiple functions.

6
 DE VELOPMENTAL & BEHAVIOR AL GENE TICS

SPLICE IT UP: Confocal image shows Dscam2 isoform B expression

in the optic lobe during mid pupal development. Colors are inverted
to highlight the complexity of neuronal projections within the brain.
How the brain makes trillions of synaptic connections using a genome
of only 20,000 genes is a major question in neuroscience. Alternative
splicing is one mechanism that can increase the number of proteins
produced by each gene. Using the Drosophila visual system model,
Kerwin et al. investigated the defects associated with mis-expression of
different Dscam2 isoforms, finding that regulated Dscam2 alternative
splicing is necessary for the proper assembly of photoreceptor synapses.
Image: Joshua Shing Shun Li.

Regulated Alternative Splicing of Drosophila Dscam2 Is Necessary for Attaining

the Appropriate Number of Photoreceptor Synapses
Sarah K. Kerwin, Joshua Shing Shun Li, Peter G. Noakes, Grace Ji-eun Shinand, and
S. Sean Millard
7
Genetics February 2018 208: 717–728
 CELLUL AR GENE TICS

A CRISPR Tagging-Based Screen Reveals

Localized Players in Wnt-Directed Asymmetric
Cell Division
Jennifer K. Heppert, Ariel M. Pani, Allyson M. Roberts, Daniel J. Dickinson, and
Bob Goldstein
Genetics March 2018 208: 1147–1164

EDITORS’ NOTE Signaling between cells is one important way that cell
divisions are oriented in tissues, yet little is known about how intercellular
signals act as spatial cues for mitotic spindle positioning. Heppert et al. used
a CRISPR-based approach to fluorescently tag a large number of candidate
proteins—23 of them—at their endogenous loci and precisely determine their
localization during a Wnt-directed asymmetric cell division in the early C.
elegans embryo. Using live imaging and classical embryology, the authors
found that members of the Wnt signaling pathway, but not canonical regulators
of astral microtubules, are asymmetric during mitotic spindle positioning.

ABSTRACT Oriented cell divisions are critical to establish and maintain

cell fates and tissue organization. Diverse extracellular and intracellular
cues have been shown to provide spatial information for mitotic spindle
positioning; however, the molecular mechanisms by which extracellular
signals communicate with cells to direct mitotic spindle positioning are largely
unknown. In animal cells, oriented cell divisions are often achieved by the
localization of force-generating motor protein complexes to discrete cortical
domains. Disrupting either these force-generating complexes or proteins that
globally affect microtubule stability results in defects in mitotic positioning,
irrespective of whether these proteins function as spatial cues for spindle
orientation. This poses a challenge to traditional genetic dissection of this
process. Therefore, as an alternative strategy to identify key proteins that act
downstream of intercellular signaling, we screened the localization of many
candidate proteins by inserting fluorescent tags directly into endogenous
gene loci, without overexpressing the proteins. We tagged 23 candidate
proteins in Caenorhabditis elegans and examined each protein’s localization
in a well-characterized, oriented cell division in the four-cell-stage embryo.
We used cell manipulations and genetic experiments to determine which cells
harbor key localized proteins and which signals direct these localizations in
vivo. We found that Dishevelled and adenomatous polyposis coli homologs
are polarized during this oriented cell division in response to a Wnt signal, but
two proteins typically associated with mitotic spindle positioning, homologs
of NuMA and Dynein, were not detectably polarized. These results suggest
an unexpected mechanism for mitotic spindle positioning in this system, they
pinpoint key proteins of interest, and they highlight the utility of a screening
approach based on analyzing the localization of endogenously tagged
proteins.
8
 COMPLE X TR AITS

A Simple Test Identifies Selection on Complex

Traits
Tim Beissinger, Jochen Kruppa, David Cavero, Ngoc-Thuy Ha, Malena Erbe, and
Henner Simianer
Genetics May 2018 209: 321–333

EDITORS’ NOTE Important traits are often controlled by a large number

of genes that each impact a small proportion of total variation; however,
the majority of tools in population genomics are designed to identify single
genes with large effects. Beissinger et al. describe an approach to identifying
selected traits controlled by many genes. Their technique uses additive
effects estimates from all available markers coupled with estimates of allele
frequency change over time. Based on simulations and analyses of maize and
chicken breeding populations, they demonstrate the power of their approach
for identifying traits controlled by many genes.

ABSTRACT Important traits in agricultural, natural, and human populations

are increasingly being shown to be under the control of many genes that
individually contribute only a small proportion of genetic variation. However,
the majority of modern tools in quantitative and population genetics, including
genome-wide association studies and selection-mapping protocols, are
designed to identify individual genes with large effects. We have developed an
approach to identify traits that have been under selection and are controlled
by large numbers of loci. In contrast to existing methods, our technique
uses additive-effects estimates from all available markers, and relates these
estimates to allele-frequency change over time. Using this information,
we generate a composite statistic, denoted , which can be used to test
for significant evidence of selection on a trait. Our test requires pre- and
postselection genotypic data but only a single time point with phenotypic
information. Simulations demonstrate that is powerful for identifying
selection, particularly in situations where the trait being tested is controlled
by many genes, which is precisely the scenario where classical approaches
for selection mapping are least powerful. We apply this test to breeding
populations of maize and chickens, where we demonstrate the successful
identification of selection on traits that are documented to have been under
selection.

9
 WORMBOOK

Recent Molecular Genetic Explorations of

Caenorhabditis elegans MicroRNAs
Victor Ambros and Gary Ruvkun
Genetics July 2018 209: 651–673

EDITORS’ NOTE WormBook is a comprehensive series of review articles

on the current state of C. elegans research. Here, Ambros and Ruvkun dive
into microRNAs, which regulate gene expression and function in almost every
process in the worm. They discuss the mutant studies that have provided
insight into microRNAs, provide an overview of microRNA regulation, and
explore ways of identifying microRNA targets.

ABSTRACT MicroRNAs are small, noncoding RNAs that regulate gene

expression at the post-transcriptional level in essentially all aspects of
Caenorhabditis elegans biology. More than 140 genes that encode
microRNAs in C. elegans regulate development, behavior, metabolism, and
responses to physiological and environmental changes. Genetic analysis
of C. elegans microRNA genes continues to enhance our fundamental
understanding of how microRNAs are integrated into broader gene regulatory
networks to control diverse biological processes, including growth, cell
division, cell fate determination, behavior, longevity, and stress responses.
As many of these microRNA sequences and the related processing
machinery are conserved over nearly a billion years of animal phylogeny, the
assignment of their functions via worm genetics may inform the functions
of their orthologs in other animals, including humans. In vivo investigations
are especially important for microRNAs because in silico extrapolation of
their functions using mRNA target prediction programs can easily assign
microRNAs to incorrect genetic pathways. At this mezzanine level of
microRNA bioinformatic sophistication, genetic analysis continues to be the
gold standard for pathway assignments.

10
 RE VIE W COLLECTIONS

YeastBook, FlyBook, and WormBook are comprehensive review

collections presenting the current state of knowledge in yeast,
Drosophila, and C. elegans research. Published by GENETICS in
partnership with each model organism community, these ongoing
collections are edited by a dedicated team of experts and cover a
broad range of topics, including methods, genetics, evolution, cell
biology, development, and much more.

YeastBook FlyBook WormBook

Editor in Chief Editor in Chief Editor in Chief

Alan G. Hinnebusch Lynn Cooley Iva Greenwald
National Institutes of Health Yale University Columbia University
Co-Editor in Chief
John R. Carlson
Yale University
Co-Editor in Chief
R. Scott Hawley
Stowers Institute
for Medical Research

11
 DE VELOPMENTAL & BEHAVIOR AL GENE TICS

Holes in the Plasma Membrane Mimic Torso-

Like Perforin in Torso Tyrosine Kinase
Receptor Activation in the Drosophila Embryo
Alessandro Mineo, Esther Fuentes, Marc Furriols, and Jordi Casanova
Genetics September 2018 210: 257–262

EDITORS’ NOTE Activation of receptor tyrosine kinases (RTKs) is critical for

many cellular processes and is therefore tightly regulated. Mineo et al. show
that mechanically induced holes in the Drosophila embryo can substitute for
the function of Torso-like (Tsl), a perforin domain-containing protein required
for the activation of RTK protein Torso. These results suggest that cell injuries
may contribute to abnormal RTK activation.

ABSTRACT Receptor tyrosine kinase (RTK) pathways play central roles in

development, and, when abnormally activated, they can lead to pathological
conditions, including oncogenesis. Thus, RTK activation, mediated by ligand
binding, is under tight control, a critical step being the conversion of an
inactive precursor into the active form of the ligand. A variety of mechanisms
have been shown to be involved in this conversion; however, little attention
has been paid to how mechanical phenomena may impinge on this process.
Here we address this issue by studying Torso, an RTK activated at both poles
of the Drosophila embryo at the blastoderm stage. Torso activation is induced
by a cleaved form of Trunk, a growth factor-like protein, but it also requires the
accumulation of the Torso-like (Tsl) protein at both ends of the blastoderm. Tsl
is the only known protein in Drosophila bearing a membrane attack complex/
perforin (MACPF) domain—a motif present in proteins involved in pore
formation at cell membranes. However, while different hypotheses have been
put forward to account for the function of Tsl in Torso receptor activation,
little is known about its molecular role and whether it indeed contributes to
membrane pore formation. Here, we show that mechanically induced holes in
the Drosophila embryo can substitute for Tsl function. These results suggest
that Tsl is required for an exchange between the interior of the Drosophila
embryo and its surrounding milieu and that mechanically induced cell injuries
may contribute to abnormal RTK activation.
.

12
 COMPLE X TR AITS

RAINBOW ROOTS Pictured left to right are eight carrot (Daucus

carota L.) phenotypes from wild to domesticated spanning over a
thousand years of carrot evolution. From left to right: white-rooted
wild accession; yellow and purple rooted landrace accessions that
represent some of the first domesticated types; white, yellow, and
orange rooted open pollinated accessions that are the direct ancestors
of modern orange carrots; and two elite orange rooted processing and
fresh market carrots. An association analysis that included more than
700 carrot accessions from around the world revealed that the Or gene,
which has not been previously identified in carrot, is a candidate for the
extraordinary level of carotenoid accumulation that characterizes this
crop. This gene was likely important in the very early stages of carrot
domestication and improvement.
Photo: Matthew Mirkes (University of Wisconsin-Madison).

Carotenoid Presence Is Associated with the Or Gene in Domesticated Carrot

Shelby L. Ellison, Claire H. Luby, Keo E. Corak, Kevin M. Coe, Douglas Senalik,
Massimo Iorizzo, Irwin L. Goldman, Philipp W. Simon, and Julie C. Dawson
Genetics December 2018 210: 1497–1508 13
 DE VELOPMENTAL & BEHAVIOR AL GENE TICS

Isolation of Aggressive Behavior Mutants in

Drosophila Using a Screen for Wing Damage
Shaun M. Davis, Amanda L. Thomas, Lingzhi Liu, Ian M. Campbell, and
Herman A. Dierick
Genetics January 2018 208: 273–282

EDITORS’ NOTE Aggressive behavior has largely been refractory to genetic

screen analysis because the required methodology is tedious and time
consuming. Davis et al. discovered that housing aggressive flies in groups
leads to noticeable wing damage over time. They used this easy-to-score
phenotype to isolate mutants with aggressive behavior, characterizing one of
the mutants and finding the causal mutation in a gene that regulates
neuronal excitability.

ABSTRACT Aggression is a complex social behavior that is widespread

in nature. To date, only a limited number of genes that affect aggression
have been identified, in large part because the complexity of the phenotype
makes screening difficult and time-consuming regardless of the species
that is studied. We discovered that aggressive group-housed Drosophila
melanogaster males inflict damage on each other’s wings, and show that
wing damage negatively affects their ability to fly and mate. Using this wing-
damage phenotype, we screened males from ~1400 chemically mutagenized
strains and found ~40 mutant strains with substantial wing damage. Five
of these mutants also had increased aggressive behavior. To identify the
causal mutation in one of our top aggressive strains, we used whole-genome
sequencing and genomic duplication rescue strategies. We identified a novel
mutation in the voltage-gated potassium channel Shaker (Sh) and show that a
nearby previously identified Sh mutation also results in increased aggression.
This simple screen can be used to dissect the molecular mechanisms
underlying aggression.

14
 DE VELOPMENTAL & BEHAVIOR AL GENE TICS

Initiation of Meiotic Development Is

Controlled by Three Post-transcriptional
Pathways in Caenorhabditis elegans
Ariz Mohammad, Kara Vanden Broek, Christopher Wang, Anahita Daryabeigi, Verena
Jantsch, Dave Hansen, and Tim Schedl
Genetics August 2018 209: 1197–1224

EDITORS’ NOTE A major transition in germ cell development is the switch

from mitotic cell cycling to entry into the meiotic developmental pathway.
Mohammad et al. report that the SCFPROM-1 substrate-specific E3 ubiquitin
ligase complex is a new regulator of meiotic entry in C. elegans, functioning
to both downregulate mitotic cell cycle protein levels and to promote
homologous chromosome pairing as a positive regulator of CHK-2. They
demonstrate that three post-transcriptional pathways function in parallel to
coordinate the transition to meiotic development in C. elegans.

ABSTRACT A major event in germline development is the transition from

stem/progenitor cells to entry into meiosis and gametogenesis. This transition
requires downregulation of mitotic cell cycle activity and upregulation of
processes associated with meiosis. We identify the Caenorhabditis elegans
SCFPROM-1 E3 ubiquitin-ligase complex as functioning to downregulate
mitotic cell cycle protein levels including cyclin E, WAPL-1, and KNL-2 at
meiotic entry and, independently, promoting homologous chromosome
pairing as a positive regulator of the CHK-2 kinase. SCFPROM-1 is thus
a novel regulator of meiotic entry, coordinating downregulation of mitotic
cell cycle proteins and promoting homolog pairing. We further show that
SCFPROM-1functions redundantly, in parallel to the previously described
GLD-1and GLD-2 meiotic entry pathways, downstream of and inhibited by
GLP-1 Notch signaling, which specifies the stem cell fate. Accordingly, C.
elegans employs three post-transcriptional pathways, SCFPROM-1-mediated
protein degradation, GLD-1-mediated translational repression, and GLD-2-
mediated translational activation, to control and coordinate the initiation of
meiotic development.

15
 DE VELOPMENTAL & BEHAVIOR AL GENE TICS

Mito-Nuclear Interactions Affecting Lifespan

and Neurodegeneration in a Drosophila Model
of Leigh Syndrome
Carin A. Loewen and Barry Ganetzky
Genetics April 2018 208: 1535–1552

EDITORS’ NOTE Mitochondrial function requires coordination between

proteins encoded in both the nuclear and mitochondrial genomes.
Genetic variation in mitochondrial genomes has been suggested to modify
phenotypes of nuclear-encoded mitochondrial mutations, but direct
evidence is scarce. Loewen and Ganetzky characterized a nuclear-encoded
mitochondrial mutant in Drosophila and show that variation in phenotypic
severity is associated with otherwise silent mitochondrial sequence variants.
Their work demonstrates that mito-nuclear interactions can impact disease
and provides a powerful experimental system to further investigate mito-
nuclear interactions.

ABSTRACT Proper mitochondrial activity depends upon proteins encoded

by genes in the nuclear and mitochondrial genomes that must interact
functionally and physically in a precisely coordinated manner. Consequently,
mito-nuclear allelic interactions are thought to be of crucial importance on
an evolutionary scale, as well as for manifestation of essential biological
phenotypes, including those directly relevant to human disease. Nonetheless,
detailed molecular understanding of mito-nuclear interactions is still lacking,
and definitive examples of such interactions in vivo are sparse. Here we
describe the characterization of a mutation in Drosophila ND23, a nuclear
gene encoding a highly conserved subunit of mitochondrial complex 1.
This characterization led to the discovery of a mito-nuclear interaction that
affects the ND23 mutant phenotype. ND23 mutants exhibit reduced lifespan,
neurodegeneration, abnormal mitochondrial morphology, and decreased
ATP levels. These phenotypes are similar to those observed in patients
with Leigh syndrome, which is caused by mutations in a number of nuclear
genes that encode mitochondrial proteins, including the human ortholog of
ND23. A key feature of Leigh syndrome, and other mitochondrial disorders, is
unexpected and unexplained phenotypic variability. We discovered that the
phenotypic severity of ND23 mutations varies depending on the maternally
inherited mitochondrial background. Sequence analysis of the relevant
mitochondrial genomes identified several variants that are likely candidates
for the phenotypic interaction with mutant ND23, including a variant affecting
a mitochondrially encoded component of complex I. Thus, our work provides
an in vivo demonstration of the phenotypic importance of mito-nuclear
interactions in the context of mitochondrial disease.

16
Receive mentoring in scientific reviewing from
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Learn more:
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17
 DE VELOPMENTAL & BEHAVIOR AL GENE TICS

Differential Expression of Histone H3.3 Genes

and Their Role in Modulating Temperature
Stress Response in Caenorhabditis elegans
Kamila Delaney, Jonathan Mailler, Joanna M. Wenda, Caroline Gabus, and
Florian A. Steiner
Genetics June 2018 209: 551–565

EDITORS’ NOTE Histone H3.3, a major variant of canonical histone H3,

is highly conserved and essential for viability or fertility in most lineages.
In C. elegans, H3.3 is expressed from five genes. Delaney et al. find that
the five genes show distinct developmental expression patterns, and their
nucleosome incorporation depends on the conserved histone chaperone
HIRA-1. Surprisingly, H3.3 is dispensable for viability in C. elegans; instead, it
plays a vital role in the response to stresses such as high temperature.

ABSTRACT Replication-independent variant histones replace canonical

histones in nucleosomes and act as important regulators of chromatin
function. H3.3 is a major variant of histone H3 that is remarkably conserved
across taxa and is distinguished from canonical H3 by just four key amino
acids. Most genomes contain two or more genes expressing H3.3, and
complete loss of the protein usually causes sterility or embryonic lethality.
Here, we investigate the developmental expression patterns of the five
Caenorhabditis elegans H3.3 homologs and identify two previously
uncharacterized homologs to be restricted to the germ line. Despite these
specific expression patterns, we find that neither loss of individual H3.3
homologs nor the knockout of all five H3.3-coding genes causes sterility
or lethality. However, we demonstrate an essential role for the conserved
histone chaperone HIRA in the nucleosomal loading of all H3.3 variants. This
requirement can be bypassed by mutation of the H3.3-specific residues
to those found in H3. While even removal of all H3.3 homologs does not
result in lethality, it leads to reduced fertility and viability in response to high-
temperature stress. Thus, our results show that H3.3 is nonessential in
C. elegans but is critical for ensuring adequate response to stress.

18
 GENE E XPRESSION

Transcription Promotes the Interaction of the

FAcilitates Chromatin Transactions (FACT)
Complex with Nucleosomes in Saccharomyces
cerevisiae
Benjamin J. E. Martin, Adam T. Chruscicki, and LeAnn J. Howe
Genetics November 2018 210: 869–881

EDITORS’ NOTE FACT (FAcilitates Chromatin Transactions) is an abundant

and conserved complex essential for cell viability. FACT binds to highly
expressed genes and facilitates transcription while maintaining chromatin
structure, but how it is targeted to these regions is unknown. In this study,
Martin et al. use high resolution analysis of FACT occupancy in S. cerevisiae
to show that the complex is targeted to transcribed regions through
preferential interaction with RNA polymerase-disrupted nucleosomes.

ABSTRACT The FACT (FAcilitates Chromatin Transactions) complex is a

conserved complex that maintains chromatin structure on transcriptionally
active genes. Consistent with this, FACT is enriched on highly expressed
genes, but how it is targeted to these regions is unknown. In vitro, FACT binds
destabilized nucleosomes, supporting the hypothesis that FACT is targeted
to transcribed chromatin through recognition of RNA polymerase (RNAP)-
disrupted nucleosomes. In this study, we used high-resolution analysis
of FACT occupancy in Saccharomyces cerevisiae to test this hypothesis.
We demonstrate that FACT interacts with nucleosomes in vivo and that its
interaction with chromatin is dependent on transcription by any of the three
RNAPs. Deep sequencing of micrococcal nuclease-resistant fragments
shows that FACT-bound nucleosomes exhibit differing nuclease sensitivity
compared to bulk chromatin, consistent with a modified nucleosome structure
being the preferred ligand for this complex. Interestingly, a subset of FACT-
bound nucleosomes may be “overlapping dinucleosomes,” in which one
histone octamer invades the ~147-bp territory normally occupied by the
adjacent nucleosome. While the differing nuclease sensitivity of FACT-bound
nucleosomes could also be explained by the demonstrated ability of FACT
to alter nucleosome structure, transcription inhibition restores nuclease
resistance, suggesting that it is not due to FACT interaction alone. Collectively,
these results are consistent with a model in which FACT is targeted to
transcribed genes through preferential interaction with RNAP-disrupted
nucleosomes.

19
 GENOME INTEGRIT Y & TR ANSMISSION

Genomic Instability Promoted by

Overexpression of Mismatch Repair Factors
in Yeast: A Model for Understanding Cancer
Progression
Ujani Chakraborty, Timothy A. Dinh, and Eric Alani
Genetics June 2018 209: 439–456

EDITORS’ NOTE Increased expression of mismatch repair proteins often

correlates with tumor aggressiveness. Chakraborty et al. report that co-
overexpression of Msh2 and Msh6 in yeast results in genome instability
phenotypes that are dependent on interaction with the replication fork
component PCNA; this overexpression also alters the cell cycle distribution
of exponentially growing cells. Overexpression of MSH factors may affect the
integrity of the DNA replication fork, causing genome instability phenotypes
that likely promote cancer progression.

ABSTRACT Mismatch repair (MMR) proteins act in spellchecker roles to

excise misincorporation errors that occur during DNA replication. Curiously,
large-scale analyses of a variety of cancers showed that increased expression
of MMR proteins often correlated with tumor aggressiveness, metastasis,
and early recurrence. To better understand these observations, we used
The Cancer Genome Atlas and Gene Expression across Normal and Tumor
tissue databases to analyze MMR protein expression in cancers. We found
that the MMR genes MSH2 and MSH6 are overexpressed more frequently
than MSH3, and that MSH2 and MSH6 are often cooverexpressed as a
result of copy number amplifications of these genes. These observations
encouraged us to test the effects of upregulating MMR protein levels
in baker’s yeast, where we can sensitively monitor genome instability
phenotypes associated with cancer initiation and progression. Msh6
overexpression (two- to fourfold) almost completely disrupted mechanisms
that prevent recombination between divergent DNA sequences by interacting
with the DNA polymerase processivity clamp PCNA and by sequestering the
Sgs1 helicase. Importantly, cooverexpression of Msh2 and Msh6 (~eightfold)
conferred, in a PCNA interaction-dependent manner, several genome
instability phenotypes including increased mutation rate, increased sensitivity
to the DNA replication inhibitor HU and the DNA-damaging agents MMS
and 4-nitroquinoline N-oxide, and elevated loss-of-heterozygosity. Msh2 and
Msh6 cooverexpression also altered the cell cycle distribution of exponentially
growing cells, resulting in an increased fraction of unbudded cells,
consistent with a larger percentage of cells in G1. These novel observations
suggested that overexpression of MSH factors affected the integrity of the
DNA replication fork, causing genome instability phenotypes that could be
important for promoting cancer progression.

20
 POPUL ATION & E VOLUTIONARY GENE TICS

Fitness Costs and Variation in Transmission

Distortion Associated with the Abnormal
Chromosome 10 Meiotic Drive System in Maize
David M. Higgins, Elizabeth G. Lowry, Lisa B. Kanizay, Philip W. Becraft, David W. Hall,
and R. Kelly Dawe
Genetics January 2018 208: 297–305

EDITORS’ NOTE The maize abnormal chromosome 10 (Ab10) meiotic drive

system causes its own preferential transmission through females, yet it is
found at low frequencies in natural populations. Higgins et al. help to explain
this observation by revealing that Ab10 has significant deleterious effects
in the homozygous state. Its selfish properties as a meiotic driver allow it
to maintain a stable presence, but its negative effects on plant productivity
at high frequencies set up an equilibrium where the chromosome is often
observed—but never fixed.

ABSTRACT Meiotic drive describes a process whereby selfish genetic

elements are transmitted at levels greater than Mendelian expectations.
Maize abnormal chromosome 10 (Ab10) encodes a meiotic drive system
that exhibits strong preferential segregation through female gametes. We
performed transmission assays on nine Ab10 chromosomes from landraces
and teosinte lines and found a transmission advantage of 62–79% in
heterozygotes. Despite this transmission advantage, Ab10 is present at low
frequencies in natural populations, suggesting that it carries large negative
fitness consequences. We measured pollen transmission, the percentage
of live pollen, seed production, and seed size to estimate several of the
possible fitness effects of Ab10. We found no evidence that Ab10 affects
pollen transmission, i.e., Ab10 and N10 pollen are transmitted equally from
heterozygous fathers. However, at the diploid (sporophyte) level, both
heterozygous and homozygous Ab10-I-MMR individuals show decreased
pollen viability, decreased seed set, and decreased seed weight. The
observed fitness costs can nearly but not entirely account for the observed
frequencies of Ab10. Sequence analysis shows a surprising amount of
molecular variation among Ab10 haplotypes, suggesting that there may be
other phenotypic variables that contribute to the low but stable equilibrium
frequencies.

21
 POPUL ATION & E VOLUTIONARY GENE TICS

Estimates of the Heritability of Human

Longevity Are Substantially Inflated due to
Assortative Mating
J. Graham Ruby, Kevin M. Wright, Kristin A. Rand, Amir Kermany, Keith Noto, Don
Curtis, Neal Varner, Daniel Garrigan, Dmitri Slinkov, Ilya Dorfman, Julie M. Granka,
Jake Byrnes, Natalie Myres, and Catherine Ball
Genetics November 2018 210: 1109–1124

EDITORS’ NOTE Ruby et al. analyzed an unprecedented amount of family

tree data from the genealogy company Ancestry and determined that the
heritability of human longevity was well below 10%, lower than the previous
estimates of 15–30%. Their findings suggest that the heritability of human
longevity has been historically over-estimated due to assortative mating.

ABSTRACT Human life span is a phenotype that integrates many aspects

of health and environment into a single ultimate quantity: the elapsed
time between birth and death. Though it is widely believed that long life
runs in families for genetic reasons, estimates of life span “heritability” are
consistently low (~15–30%). Here, we used pedigree data from Ancestry
public trees, including hundreds of millions of historical persons, to estimate
the heritability of human longevity. Although “nominal heritability” estimates
based on correlations among genetic relatives agreed with prior literature,
the majority of that correlation was also captured by correlations among
nongenetic (in-law) relatives, suggestive of highly assortative mating around
life span-influencing factors (genetic and/or environmental). We used structural
equation modeling to account for assortative mating, and concluded that the
true heritability of human longevity for birth cohorts across the 1800s and
early 1900s was well below 10%, and that it has been generally overestimated
due to the effect of assortative mating.

22
 COMMENTARY

Tread Lightly Interpreting Polygenic Tests of

Selection
John Novembre and Nicholas H. Barton
Genetics April 2018 208: 1351–135

EDITORS’ NOTE Polygenic tests of selection afford the opportunity for

evolutionary geneticists to better understand how traits evolve through many
very small changes in allele frequency. In this Commentary on Racimo et al.
(2018), Novembre and Barton urge scientists to exercise caution as they draw
conclusions from these tests, since the results are open to misinterpretation—
and are often discussed outside of the research community. They explain
the caveats and limitations of such studies in the hopes of improving the
accuracy of discussion around polygenic trait selection.

Commentary on
Detecting Polygenic Adaptation in Admixture Graphs
Fernando Racimo, Jeremy J. Berg, and Joseph K. Pickrell
Genetics April 2018 208: 1565-1584

ABSTRACT In the April 2018 issue of GENETICS, a new method for detecting
natural selection on polygenic traits is developed and applied to several
human examples (Racimo et al. 2018). By definition, many loci contribute to
variation in polygenic traits, and a challenge for evolutionary geneticists has
been that these traits can evolve by small, nearly undetectable shifts in allele
frequencies across each of many, typically unknown, loci. Recently, a helpful
remedy has arisen. Genome-wide association studies (GWAS) have been
illuminating sets of loci that can be interrogated jointly for changes in allele
frequencies. By aggregating small signals of change across many such loci,
directional natural selection is now in principle detectable using genetic data,
even for highly polygenic traits. This is an exciting arena of progress – with
these methods, tests can be made for selection associated with traits, and
we can now study selection in what may be its most prevalent mode. The
continuing fast pace of GWAS publications suggest there will be many more
polygenic tests of selection in the near future, as every new GWAS is an
opportunity for an accompanying test of polygenic selection. However, it is
important to be aware of complications that arise in interpretation, especially
given that these studies may easily be misinterpreted both in and outside the
evolutionary genetics community. Here, we provide context for understanding
polygenic tests and urge caution regarding how these results are interpreted
and reported upon more broadly.

23
 POPUL ATION & E VOLUTIONARY GENE TICS

Repeated Selection of Alternatively Adapted

Haplotypes Creates Sweeping Genomic
Remodeling in Stickleback
Susan Bassham, Julian Catchen, Emily Lescak, Frank A. von Hippel, and
William A. Cresko
Genetics July 2018 209: 921–939

EDITORS’ NOTE After the catastrophic 1964 Alaskan earthquake, marine

stickleback fish colonized newly created ponds on seismically uplifted
islands. Bassham and Catchen et al. show that, in these natural replicate
populations, as much as a quarter of the genome changed in the first
dozens of generations, and identical haplotypes were repeatedly selected
from standing genetic variation. Marine fish harbor significant frequencies of
these genotypes, providing potential for rapid exploitation of new freshwater
habitats. These findings give insight into the adaptive capacity of species that
exist across variable environments, particularly during accelerating climate
and land-use change.

ABSTRACT Heterogeneous genetic divergence can accumulate across the

genome when populations adapt to different habitats while still exchanging
alleles. How long does diversification take and how much of the genome is
affected? When divergence occurs in parallel from standing genetic variation,
how often are the same haplotypes involved? We explore these questions
using restriction site-associated DNA sequencing genotyping data and show
that broad-scale genomic repatterning, fueled by copious standing variation,
can emerge in just dozens of generations in replicate natural populations of
threespine stickleback fish (Gasterosteus aculeatus). After the catastrophic
1964 Alaskan earthquake, marine stickleback colonized newly created ponds
on seismically uplifted islands. We find that freshwater fish in these young
ponds differ from their marine ancestors across the same genomic segments
previously shown to have diverged in much older lake populations. Outside
of these core divergent regions the genome shows no population structure
across the ocean–freshwater divide, consistent with strong local selection
acting in alternative environments on stickleback populations still connected
by significant gene flow. Reinforcing this inference, a majority of divergent
haplotypes that are at high frequency in ponds are detectable in the sea,
even across great geographic distances. Building upon previous population
genomics work in this model species, our data suggest that a long history of
divergent selection and gene flow among stickleback populations in oceanic
and freshwater habitats has maintained polymorphisms of alternatively
adapted DNA sequences that facilitate parallel evolution.

24
 ME THODS, TECHNOLOGY, & RESOURCES

SPONGE TOOLS: Suberites domuncula, a bright orange demosponge, colonizes

gastropod shells that are in turn occupied by hermit crabs. The picture features
two interacting hermit crabs and their sponge symbionts in a sea water aquarium.
Despite a long history of sponges as experimental model systems, functional
molecular studies are still very difficult to perform in these animals. Revilla-i-
Domingo et al. used Suberites domuncula to establish the first transgenesis system
for research in a sponge species.
Photo: Roger Revilla-i-Domingo.

Establishment of Transgenesis in the Demosponge Suberites domuncula

Roger Revilla-i-Domingo, Clara Schmidt, Clara Zifko, and Florian Raible
Genetics October 2018 210: 2 435–44 25
 STATISTICAL GENE TICS & GENOMICS

Accurate Genomic Prediction of Human Height

Louis Lello, Steven G. Avery, Laurent Tellier, Ana I. Vazquez, Gustavo de los Campos,
and Stephen D. H. Hsu
Genetics October 2018 210: 477–497

EDITORS’ NOTE Hsu et al. used machine learning to analyze almost half
a million genomes. They produced, for the first time, accurate genomic
predictors for complex traits such as height, bone density, and educational
attainment. From DNA alone, adult height predictions are accurate to within
roughly one inch. These methods can also be used to estimate how much
genomic data is required for prediction of other complex traits, such as
disease risks.

ABSTRACT We construct genomic predictors for heritable but extremely

complex human quantitative traits (height, heel bone density, and educational
attainment) using modern methods in high dimensional statistics (i.e., machine
learning). The constructed predictors explain, respectively, ~40, 20, and
9% of total variance for the three traits, in data not used for training. For
example, predicted heights correlate ~0.65 with actual height; actual heights
of most individuals in validation samples are within a few centimeters of the
prediction. The proportion of variance explained for height is comparable
to the estimated common SNP heritability from genome-wide complex trait
analysis (GCTA), and seems to be close to its asymptotic value (i.e., as sample
size goes to infinity), suggesting that we have captured most of the heritability
for SNPs. Thus, our results close the gap between prediction R-squared and
common SNP heritability. The ~20k activated SNPs in our height predictor
reveal the genetic architecture of human height, at least for common variants.
Our primary dataset is the UK Biobank cohort, comprised of almost 500k
individual genotypes with multiple phenotypes. We also use other datasets
and SNPs found in earlier genome-wide association studies (GWAS) for out-
of-sample validation of our results.

26
 STATISTICAL GENE TICS & GENOMICS

Inferring Continuous and Discrete Population

Genetic Structure Across Space
Gideon S. Bradburd, Graham M. Coop, and Peter L. Ralph
Genetics September 2018 210: 33–52

EDITORS’ NOTE Individuals that live close together are, on average,

more genetically similar than individuals sampled farther apart, but current
statistical methods for inferring population structure cannot accommodate
spatial information, leading to the assignment of continuous variation to
discrete clusters. Here, Bradburd et al. report a new method for categorizing
natural genetic variation that describes variation as a combination of
continuous and discrete patterns. They demonstrate that this method can
capture patterns in population genomic data without resorting to splitting
populations.

ABSTRACT A classic problem in population genetics is the characterization

of discrete population structure in the presence of continuous patterns of
genetic differentiation. Especially when sampling is discontinuous, the use of
clustering or assignment methods may incorrectly ascribe differentiation due
to continuous processes (e.g., geographic isolation by distance) to discrete
processes, such as geographic, ecological, or reproductive barriers between
populations. This reflects a shortcoming of current methods for inferring
and visualizing population structure when applied to genetic data deriving
from geographically distributed populations. Here, we present a statistical
framework for the simultaneous inference of continuous and discrete patterns
of population structure. The method estimates ancestry proportions for
each sample from a set of two-dimensional population layers, and, within
each layer, estimates a rate at which relatedness decays with distance. This
thereby explicitly addresses the “clines versus clusters” problem in modeling
population genetic variation, and remedies some of the overfitting to which
nonspatial models are prone. The method produces useful descriptions of
structure in genetic relatedness in situations where separated, geographically
distributed populations interact, as after a range expansion or secondary
contact. We demonstrate the utility of this approach using simulations and by
applying it to empirical datasets of poplars and black bears in North America.

27
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