\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,greek,english]{babel}



\usepackage{float}








\begin{document}

\title{Genome-wide selection signal analysis of Australian Boer goat by using
insertion/deletion variants}



\author[1]{ying yuan}%
\author[1]{Bai-Gao Yang}%
\author[1]{yongmeng he}%
\author[1]{xinghai Duan}%
\author[1]{weiyi zhang}%
\author[2]{Ri-Su Na}%
\author[1]{yanguo Han}%
\author[1]{Yan Zeng}%
\author[1]{Yongfu Huang}%
\author[3]{Yong-Ju Zhao}%
\author[4]{Zhong-Quan Zhao}%
\author[1]{shizhi wang}%
\author[1]{guangxin e}%
\affil[1]{Southwest University}%
\affil[2]{Chongqing Engineering Research Centre for Herbivores Resource Protection and Utilization, Southwest University}%
\affil[3]{College of Animal Science and Technology, Chongqing Key Laboratory of Forage \& Herbivore, Chongqing Engineering Research Centre for Herbivores Resource Protection and Utilization, Southwest University}%
\affil[4]{Chongqing Key Laboratory of Forage \& Herbivore, Chongqing Engineering Research Centre for Herbivores Resource Protection and Utilization, Southwest University}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Breed selection for commercial goat is needed for production efficiency,
growth trait alteration, and improved livestock quality. Boer goat is
famous for its stable production performance, fast growth rate, and high
meat production. Detecting selective signatures in its genome can
elucidate selection mechanisms for its economic and adaptive traits. In
this study, 1,122,858 InDels were identified based on the whole genomes
of 46 Australian Boer goats and 81 worldwide local goats. FST was used
to identify the candidate selection signatures in 127 goats. A total of
11229 InDels were obtained from the top1\% of all inDels, and 1239
candidate genes were annotated. A total of 1193 and 476 candidate genes
were involved in 4726 GO terms and 299 KEGG pathways, respectively. Many
genes were related to muscle development (MEF2C, MAPK14, TMOD1 etc.),
reproduction (SRD5A1, FBXW11, DMRT1 etc.), immunity (CD200, SGK1, IL17RB
etc.) and metabolism (INSR, STXBP3, H6PD etc.). The results provide
novel and important insights into the genetic basis of selection in Boer
goat and may be useful for goat molecular breeding.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Boer goat, which was first domesticated in South Africa in the early
19th century, has attracted worldwide attention due to its stable
production performance, fast growth rate, and high meat production
(Casey et al., 1998). Owing to the extensive introduction and breeding
of Boer goats in worldwide, comprehensive and detailed studies have been
conducted on various characteristics of Boer goat. Many studies have
successively explored their adaptability, growth performance, and hybrid
improvement. Particularly, many dominant genotypes of economic traits
due to long-term selection have been discovered (Yang et al., 2011;
Silveira et al., 2002).

Insertion/deletion markers (InDels) are a kind of structural variation
widely studied in various biology fields. For example, an 8 bp
duplicated frameshift insertion in \emph{FOXF1} is linked to alveolar
capillary dysplasia associated with pulmonary vein dislocation in human
(Karolak et al., 2019). A 1,423 bp InDel in the cis-regulatory region of
LanFTc1 is related to the vernalization and flowering time
of\emph{Lupinus angustifolius} (Taylor et al., 2019). A 49 bp deletion
in the 3'-\selectlanguage{english}untranslated region (UTR) of the \emph{MTNA} gene is
correlated to increased oxidative stress tolerance in \emph{Drosophila}
(Ramnarine et al., 2019). In domestic animals, a bounteously InDel is
connected to various economic traits, such as litter size (Li et al.,
2020; Akhatayeva et al., 2020;), reproduction (Chen et al., 2019),
growth (Zhang et al., 2019; Wang et al., 2019; Li et al., 2020; Cui et
al., 2019), milk (Ju et al., 2020). Especially in goat, abundant results
have been obtained in this area. For example, 11 and 14 bp InDels within
the\emph{CSN1S1} and \emph{CMTM2} genes are substantially associated
with litter size (Kang et al., 2019; Wang et al., 2018). InDels within
intron 2 of goat \emph{IGF2BP1} and the UTRs are remarkably associated
with their growth traits (Wang et al., 2020). An 11 bp InDel
polymorphism within the \emph{CSN1S1} gene is associated with milk
performance and body measurement traits (Zhang et al., 2019).

As a special meat breed, Boer goat has experienced long-term artificial
selection. Owing to its extremely outstanding growth performance, this
domestic animal is an important natural model in studies on artificial
breeding. In this work, InDel mutations from Boer goats were
investigated to determine potential InDel variants by using genome
re-sequencing technology. The results provide a theoretical basis for
the study of genetic mechanisms and support the valuable molecular
genetic markers for the economic traits and molecular breeding of goat
in the future.

\textbf{METHODS AND MATERIALS}

Genomes (\textgreater{}10\selectlanguage{ngerman}×depth) of 46 Australian Boer goats (case
group) were obtained from our unpublished parallel projects
(PRJNA671542). For the control group dataset, 81 published deeply
sequenced genomes of indigenous goats (non-specialized meat) from
Europe, Asia, and Africa were applied. Information on all samples is
shown in S Table1.

High-quality reads (HQRs) were initially filtered by removing the
adapter, low-quality raw paired reads, and reads with an N ratio greater
than 10\%. The number of bases with a mass value of Q\selectlanguage{english}[?]20 was ensured to
be more than 50\% of the entire read to achieve HQRs. HQRs were aligned
to the goat reference genome (ASR1) using BWA (0.7.17-r1188 version).
The resulting sequence alignment/map format (SAM) files were converted
to Binary Alignment/Map (BAM) files by using samtools
(Etherington\emph{et al.,} 2015) and picard (2.23.6 version). InDel
variant was detected with GATK (version 4.1.9.0) Unified Genotyper. The
InDels were filtered for quality purposes by considering the following
standards: (filter- QD \textless{} 2.0 \textbar{}\textbar{} FS
\textgreater{} 60.0 \textbar{}\textbar{} MQRankSum \textless{} -12.5
\textbar{}\textbar{} ReadPosRankSum \textless{} -8.0
\textbar{}\textbar{} SOR \textgreater{} 3.0 \textbar{}\textbar{} MQ
\textless{} 40.0). The following secondary filtered standard was applied
to select high-quality InDEls: --max-missing 1 --max-alleles 2
--min-alleles 2 --maf 0.05. InDels exhibiting segregation distortion or
sequencing errors were discarded.

The selective sweep of each variant was quantified according to
F\textsubscript{ST} (Hudson et al., 1992), which was calculated for each
InDel signal using VCFtools (version 0.1.16) and sweep regions with top
1\% threshold used for next analysis. The annotation of each InDel
physical position and attribution gene was determined by ANNOVAR (Wang
et al., 2010).

KOBAS 3.0 online tool ( Zeng et al., 2019) was utilized to annotate the
candidate genes for Gene Ontology (GO) and Kyoto Encyclopedia of Genes
and Genomes (KEGG). Hypergeometric test was conducted on significantly
enriched GO and KEGG terms based on the number of enriched genes. The
calculated P value underwent corrected P-value, with corrected
P-value\selectlanguage{english}[?]0.05 set as a threshold.

\textbf{RESULTS}

A total of 1,122,858 InDels were obtained from the genome of127 goats.
Most of these InDels were found in intergenic (63.8430\%) and intron
(29.7546\%), and some were located in UTR3 (0.4220\%), exon region
(0.1584\%) and UTR5 (0.0636\%) (Figure 1). The InDels located in the
exon region include 1,065 (59.6973\%) deletion mutations, which are
composed of 673 (37.72\%) frameshift mutations and 392 (21.9730\%)
non-frameshift mutations, and 614 (34.417\%) insertion mutations, which
are composed of 446 (25\%) frameshift mutations and 168 (9.4170\%)
non-frameshift mutations. A total of 105 (5.886\%) InDel variants were
located in the initiation/ termination code.

The F\textsubscript{ST} value of 1,122,858 InDels between case and
control group was obtained (Figure 2). A total of 11,229 InDels with
high signal were collected according to the top 1\% threshold of
F\textsubscript{ST} statistical parameters
(F\textsubscript{ST}\selectlanguage{english}[?]0.623043, S Table 2).

Then 3,488 of that 11,229 InDels which distributed in the exon, intron,
3'UTRn and 5'UTR region were extracted for candidate gene annotation.
Finally, 1,239 candidate genes were annotated. In addition, 1,193
candidate genes were enriched to 4,726 GO terms (S Table 3), and the top
20 significantly enriched GO terms are shown in Figure 3. The protein
binding GO terms (\emph{ZCCHC10} , \emph{NCBP1} , \emph{WLS} , etc.)
with the largest number of genes were selected, and 791 candidate genes
was enriched.

94 candidate genes were enriched in 88 GO terms related to muscle
development. In particular, 36 GO terms were related to skeletal muscle
development, skeletal muscle cell differentiation (\emph{MEF2C}
,\emph{ZNF689} ), and skeletal muscle tissue development (\emph{MAPK14}
); 39 GO terms were related to myocardial development and cardiac muscle
cell proliferation (\emph{TGFBR3} , \emph{TGFB2} , and \emph{TENM4} );
and 19 GO terms were related to smooth muscle development, such as in
the positive regulation of vascular associated smooth muscle cell
proliferation (\emph{GNAI3} ). Enrichment was also observed in a large
number of GO terms related to immune cells, such as B cell proliferation
(\emph{MEF2C} , \emph{HSPD1} , \emph{LEF1} , \emph{BCL2} ), T cell
differentiation (\emph{VAV1} , \emph{RUNX2} , \emph{PTPN22}
,\emph{ZAP70} ), and positive regulation of immune response
(\emph{TGFB2} ,\emph{RSAD2} ). Sixty-two reproductive function-relative
GO terms were also enriched, such as spermatogenesis (\emph{LRGUK} ),
which is related to germ cell development and differentiation, and
estrogen receptor activity (\emph{LEF1} , \emph{ESR1} ), which is
related to reproductive hormones. A large number of GO terms related to
metabolism were also enriched, such as the protein catabolic process
(\emph{LNPEP} ,\emph{P2RX7} , \emph{RNF165} ), amino acid metabolism
(\emph{UCHL3} ), glycerolipid metabolism (\emph{DGKH} ), and fatty acid
metabolism (\emph{LCP1)} .

KEGG results showed that 476 candidate genes were enriched to 299 KEGG
signaling pathways, 98 of which were significantly enriched (corrected P
\textless{}0.05, S Table 4). Information on the top 20 significant KEGG
enrichment pathways is shown in Figure 4. The 29 candidate genes were
significantly enriched in two signaling pathways related to muscle
regulation, namely, vascular smooth muscle contraction (\emph{ACTA2}
,\emph{MYH11} , \emph{PRKCB} , etc.) and cardiac muscle contraction
(\emph{RYR2} , \emph{SLC9A, CASQ2} etc.). In addition, 45 candidate
genes were enriched in 7 signaling pathways related to reproduction,
such as GnRH signaling pathway (\emph{PLCB1} , \emph{PRKCB} , and
\emph{PLCB4} ). Multiple signaling pathways related to growth and
development were also enriched, such as cGMP-PKG signaling pathway
(\emph{NFATC1} ,\emph{PLCB3} , and \emph{PLCB4} ). A large number of
immune-related signaling pathways were also enriched, such as NF-kappa B
signaling pathway (\emph{TRAF6} , \emph{IL1R1} , and \emph{ERC1} ). Many
metabolism relative pathways were also enriched, such as insulin
signaling pathways (\emph{RPTOR} , \emph{PPP1CC} , and \emph{PRKAG2} ),
ether lipid metabolism (\emph{PLA2G4A} , \emph{PLA2G4,} and
\emph{PLA2G4E} ), and beta-alanine metabolism (\emph{EHHADH} ,
\emph{HIBCH} , \emph{CNDP1} , and \emph{DPY} ).

\textbf{DISCUSSION}

InDel mutations related to economic traits have been investigated in
domestic animals such as pigs (Jung et al., 2020; Zhang et al., 2019),
cattle (Zhou et al., 2019; Xu et al., 2018), and sheep (Wu et al., 2020;
Zhao et al., 2018), indicating that InDel has a non-negligible role in
animal breeding. In this study, various candidate genes for economic
traits and adaptive traits of animals have been identified. In
particular, 94 candidate genes were found to be related to muscle
development (such as \emph{MEF2C} , \emph{TCF4} , \emph{MAPK14} ,
and\emph{DDX17} ).

Myocyte enhancer factor 2C (\emph{MEF2C} ) is widely involved in the
development of heart and skeletal muscle during the embryonic stage. The
synergistic action between \emph{MEF2C} and the \emph{MYoD} family
factors promote the development of skeletal muscle during the embryonic
process, and \emph{MEF2C} can regulate cell proliferation by acting as
the endpoint of the intracellular signaling pathway regulated by various
growth factors (Black et al., 1998). \emph{MEF2C} also exhibits DNA
binding activity in muscles and is highly expressed in muscle cells
during embryonic formation to regulate muscle development and
differentiation by interacting with muscle-derived bHLH protein, thyroid
hormone receptor, \emph{PEA3} , and \emph{PDP1} (Pozarska et al., 2016).
As a marker of muscle connective tissue fibroblasts, transcription
factor 4 (\emph{TCF4} ) can regulate the development of slow and fast
muscles and promote the conversion of fetuses to adult muscles (Mathew
et al., 2011). Tumor protein p73 (\emph{TP73} ) is involved in the
regulation of cell apoptosis (Stiewe et al., 2001), polyciliogenesis
(Fujitani et al., 2017), germ cell maturation (Santos et al., 2018), and
multiple biological processes (Nemajerova et al., 2019).
Thus,\emph{TP73} plays an important role in animal development and
homeostasis maintenance.

DEAD box RNA helicase 17 (DEAD-box helicase 17, \emph{DDX17} ) regulates
gene expression and transcription factor activity (Bourgeois et al.,
2016). \emph{DDX17} is an activator of \emph{MyOD} , which regulates
skeletal muscle development (Legerlotz et al., 2008).
\emph{DDX17}knockdown hinders skeletal muscle development and
differentiation (Caretti et al., 2006). Mitogen-activated protein kinase
14 (\emph{MAPK14} ) belongs to the MAP kinase family and is an important
factor in biological development. \emph{MAPK14} promotes cell
proliferation and activation by inhibiting the differentiation of
vascular smooth muscles during vascular injury. Pro-inflammatory gene
expression participates in the repair of blood vessels (Wu et al.,
2019). In addition, \emph{MAPK14} is involved in muscle atrophy by
direct phosphorylating and activating Bcl-2 family member \emph{Bax} via
mitochondrial-dependent pathway, thus resulting in muscle fiber death
(Wissing et al., 2014).

This work also screened many candidate genes related to germ cell
development and reproductive hormone regulation, such as \emph{SRD5A1}
,\emph{FBXW11} , \emph{DMRT1} , \emph{CXADR} , and \emph{RPTOR} . Early
studies have isolated steroid 5 alpha-reductase 1 (\emph{SRD5A1} ) from
rat liver and found that it is one of the three forms of steroid
5\selectlanguage{greek}α-\selectlanguage{english}reductase (Russell et al., 1994). \emph{SRD5A1} is involved in the
metabolism of estrogen and androgen. The catalytic substrates
of\emph{SRD5A1} include testosterone, progesterone, androstenedione,
epinephrine -T, cortisol, aldosterone, and deoxycorticosterone. This
enzyme catalyzes the conversion of testosterone into stronger androgen:
5\selectlanguage{greek}α-\selectlanguage{english}di hydrotestosterone (\emph{DHT} ). Therefore, \emph{SRD5A1} plays an
important role in mammalian stress, immune system regulation, and
reproduction (Han et al., 2021). F-box and WD repeat domain containing
11 (\emph{FBXW11} ), a member of the F-box protein family and a part of
the ubiquitin ligase complex, is important in the regulation of
ubiquitin-dependent spermatogenesis. The mRNA level of \emph{FBXW11} is
positively correlated with sperm motility (Liu et al., 2021).

Double sex and mab-3 related transcription factor 1 (\emph{DMRT1} ) is
involved in the sex determination of vertebrates. The functional lack
of\emph{DMRT1} in mice can lead to excessive proliferation of sertoli
cells without further differentiation in the testis, leading to germ
cell loss (Raymond et al., 2000). Knocking out the \emph{DMRT1} in the
sertoli cells in mice will activate \emph{FOXL2} , which in turn causes
the Sertoli cells to be reprogrammed into granular cells and the
testicular tissue to transform into an ovarian-like morphology (Matson
et al., 2011). As a member of the adhesion receptor tight junction
protein family, CXADR Ig-like cell adhesion molecule (\emph{CXADR} )
plays an important role in embryonic development. Its absence causes
embryonic development to stagnate in morula (Kwon et al., 2015).
Regulatory associated protein of MTOR complex 1 (\emph{RPTOR} ) encodes
the MTOR complex regulatory-related protein and is a part of the mTORC1
complex, which is important in the maintenance and renewal of mouse
spermatogonia (Serra et al., 2019).

Some candidate genes related to immune regulation were also identified.
CD200 molecule (\emph{CD200} ) is widely distributed on the surface of
myeloid immune cells, such as thymocytes, B cells, and macrophages
(Barclay et al., 1981). \emph{CD20} 0 can combine with CD200R to
participate in immune regulation. The \emph{CD200} knockout in mice
increases the activity of macrophages and cell lineage and disrupts the
immune balance of body (Hoek et al., 2000). Serum/glucocorticoid
regulated kinase 1 (\emph{SGK1} ) plays an important role in cellular
stress response. \emph{SGK1} mediates the regulation of glucocorticoid
hormone and inhibits the proliferation of progenitor cells by increasing
glucocorticoid hormone receptor phosphorylation (Anacker et al., 2013).
Interleukin 17 receptor B (\emph{IL17RB} ) exhibits immunomodulatory
activity, and its expression is up-regulated in patients with rhinitis
(Matsumoto et al., 2011). \emph{IL17RB} also participates in the
regulation of inflammatory response by mediating NF-kappa B activation
and IL8 production (Ruskin et al., 2012).

In this study, many genes related to metabolism were observed
(e.g.,\emph{INSR, STXBP3, H6PD,} and \emph{APOE} ). Insulin regulates
the body's glucose, protein, and fat homeostasis. As the insulin
receptor,\emph{INSR} participates in insulin signaling pathway
(Mukherjee et al., 2009). When the \emph{INSR} gene is knocked down,
insulin cannot perform function normally in the liver of mice, thus
leading to the gradual deterioration of liver function (Okamoto et al.,
2005). Variations in\emph{INSR} cause insulin resistance syndrome and
Donohue syndrome in multiple species (Reaven et al., 2005). The
combination between\emph{STXBP3} (syntaxin binding protein 3) and
syntaxin 4 regulates insulin in peripheral tissues (Jewell et al.,
2010). Mice with\emph{STXBP3} homozygous knockout cannot survive,
whereas those with\emph{STXBP3} heterozygous knockout exhibit reduced
insulin secretion and gradually become glucose intolerant when fed with
a high-calorie diet rich in fat and carbohydrates (Oh et al. 2005).
Hexose-6-phosphate dehydrogenase/glucose 1-dehydrogenase (\emph{H6PD} )
is involved in cell biochemical reactions and can mediate the
regeneration of glucocorticoids (Zhang et al., 2009). \emph{H6PD}
knockout in mice reduces their sensitivity to glucocorticoids, which in
turn increases insulin sensitivity and glucose uptake in muscles, thus
eventually leading to severe skeletal myopathy (Lavery et al., 2008).
Apolipoprotein E (\emph{APOE} ) encodes apolipoprotein and is one of the
transport carriers of chylomicrons. \emph{APOE} mediates lipoprotein
catabolism and promotes the hydrolysis and clearance of soluble A\selectlanguage{greek}β
\selectlanguage{english}protein (Jiang et al., 2008). Its abnormalities lead to endothelial cell
atherosclerosis (Nakashima et al., 1998) and central nervous system
defects (Masliah et al., 1995).

\textbf{CONCLUSION}

A total of 1,122,858 InDels were detected based on the whole genome
resequencing data of 46 Australian Boer goats and 81 local goats. Among
which, 11,229 candidate InDels with top 1\% high signal were screened,
and 1,239 candidate genes were annotated. Gene enrichment experiment
identified important genes from muscle development, reproduction,
immunity, and metabolism. The results provide a theoretical basis for
the study of related genetic mechanisms in goats and valuable foundation
for molecular breeding in goats.

\textbf{Data Availability Statement}

Sequencing data generated in this study were obtained from our
unpublished parallel projects (PRJNA671542).

\textbf{COMPETING INTERESTS}

The authors declare that they have no competing interests.

\textbf{Author Contributions}

Conceptualization, Ying Yuan and Guangxin E; Data curation, Ying Yuan
and Baigao Yang; Formal analysis, Ying Yuan and Yongmeng He;
Investigation, Ying Yuan, Xinhai Duan and Weiyi Zhang; Methodology,
Ri-Su Na ,Yanguo Han, Yan Zeng, Guangxin E; Project administration,
Yongju Zhao and Zhong-Quan Zhao; Resources, Yong-Fu Huang; Software,
Ying Yuan; Writing -- original draft, Ying Yuan and Baigao Yang; Writing
-- review \& editing, shizhi wang and Guangxin E. All authors read and
approved the manuscript.

\textbf{ACKNOWLEDGEMENTS}

This work was supported by the National Key R\&D Program of China (No.
2018YFD0502000), Characteristic Germplasm Resources Population Selection
and Innovation on Mutton Sheep and Goats (No. 2015BAD03B05), National
Natural Science Foundation of China (No. 31172195).

\textbf{Institutional Review Board Statement}

The experimental conditions of this study were approved by the Committee
on the Ethics of Animal Experiments of Southwest University (No.
{[}2007{]} 3) and the Animal Protection Law of China.

\textbf{REFERENCES}

\begin{enumerate}
\tightlist
\item
  Akhatayeva Z, Mao C, Jiang F, Pan C, Lin C, Hao K, Lan T, Chen H,
  Zhang Q, Lan X. Indel variants within the PRL and GHR genes associated
  with sheep litter size. Reprod Domest Anim. 2020 Nov;55(11):1470-1478.
\item
  Anacker C, Cattaneo A, Musaelyan K, Zunszain PA, Horowitz M, Molteni
  R, Luoni A, Calabrese F, Tansey K, Gennarelli M, Thuret S, Price J,
  Uher R, Riva MA, Pariante CM. Role for the kinase SGK1 in stress,
  depression, and glucocorticoid effects on hippocampal neurogenesis.
  Proc Natl Acad Sci U S A. 2013 May 21;110(21):8708-13.
\item
  Black BL, Olson EN. Transcriptional control of muscle development by
  myocyte enhancer factor-2 (MEF2) proteins. Annu Rev Cell Dev Biol.
  1998;14:167-96.
\item
  Bourgeois, C.F.; Mortreux, F.; Auboeuf, D. The multiple functions of
  RNA helicases as drivers and regulators of gene expression. Nat Rev
  Mol Cell Biol 2016, 17, 426-438.
\item
  Barclay, A.N. Different reticular elements in rat lymphoid tissue
  identified by localization of Ia, Thy-1 and MRC OX 2 antigens.
  Immunology 1981, 44, 727.
\item
  Casey N, Van Niekerk HWA, The Boer goat. I. Origin, adaptability,
  performance testing, reproduction and milk. Small Rumin
  Res1988,1:291--302.
\item
  Cui W, Liu N, Zhang X, Zhang Y, Qu L, Yan H, Lan X, Dong W, Pan C. A
  20-bp insertion/deletion (indel) polymorphism within the CDC25A gene
  and its associations with growth traits in goat. Arch Anim Breed. 2019
  Jun 17;62(1):353-360.
\item
  Caretti G, Schiltz RL, Dilworth FJ, Di Padova M, Zhao P, Ogryzko V,
  Fuller-Pace FV, Hoffman EP, Tapscott SJ, Sartorelli V. The RNA
  helicases p68/p72 and the noncoding RNA SRA are coregulators of MyoD
  and skeletal muscle differentiation. Dev Cell. 2006 Oct;11(4):547-560.
\item
  Chen M, Wang J, Liu N, Cui W, Dong W, Xing B, Pan C. Pig SOX9:
  Expression profiles of Sertoli cell (SCs) and a functional 18 bp indel
  affecting testis weight. Theriogenology. 2019 Oct 15;138:94-101.
\item
  Etherington GJ, Ramirez-Gonzalez RH, MacLean D. bio-samtools 2: a
  package for analysis and visualization of sequence and alignment data
  with SAMtools in Ruby. Bioinformatics. 2015 Aug 1;31(15):2565-7.
\item
  Fujitani M, Sato R, Yamashita T. Loss of p73 in ependymal cells during
  the perinatal period leads to aqueductal stenosis. Sci Rep. 2017 Sep
  20;7(1):12007.
\item
  Hudson RR, Slatkin M, Maddison WP. Estimation of levels of gene flow
  from DNA sequence data. Genetics. 1992 Oct;132(2):583-9.
\item
  Hoek RM, Ruuls SR, Murphy CA, Wright GJ, Goddard R, Zurawski SM, Blom
  B, Homola ME, Streit WJ, Brown MH, Barclay AN, Sedgwick JD.
  Down-regulation of the macrophage lineage through interaction with OX2
  (CD200). Science. 2000 Dec 1;290(5497):1768-1771.
\item
  Han Y, Zhuang Q, Sun B, Lv W, Wang S, Xiao Q, Pang B, Zhou Y, Wang F,
  Chi P, Wang Q, Li Z, Zhu L, Li F, Deng D, Chiang YC, Li Z, Ren R.
  Crystal structure of steroid reductase SRD5A reveals conserved steroid
  reduction mechanism. Nat Commun. 2021 Jan 19;12(1):449.
\item
  Ju X, Huang X, Zhang M, Lan X, Wang D, Wei C, Jiang H. Effects of
  eight InDel variants in FHIT on milk traits in Xinjiang brown cattle.
  Anim Biotechnol. 2020 May 13:1-9.
\item
  Jung K, Saif LJ, Wang Q. Porcine epidemic diarrhea virus (PEDV): An
  update on etiology, transmission, pathogenesis, and prevention and
  control. Virus Res. 2020 Sep;286:198045.
\item
  Jewell JL, Oh E, Thurmond DC. Exocytosis mechanisms underlying insulin
  release and glucose uptake: conserved roles for Munc18c and syntaxin
  4. Am J Physiol Regul Integr Comp Physiol. 2010 Mar;298(3):R517-31.
\item
  Jiang Q, Lee CY, Mandrekar S, Wilkinson B, Cramer P, Zelcer N, Mann K,
  Lamb B, Willson TM, Collins JL, Richardson JC, Smith JD, Comery TA,
  Riddell D, Holtzman DM, Tontonoz P, Landreth GE. ApoE promotes the
  proteolytic degradation of Abeta. Neuron. 2008 Jun 12;58(5):681-693.
\item
  Karolak JA, Bacolla A, Liu Q, Lantz PE, Petty J, Trapane P, Panzer K,
  Totapally BR, Niu Z, Xiao R, Xie NG, Wu LR, Szafranski P, Zhang DY,
  Stankiewicz P.A recurrent 8 bp frameshifting indel in FOXF1 defines a
  novel mutation hotspot associated with alveolar capillary dysplasia
  with misalignment of pulmonary veins.Am J Med Genet A. 2019
  Nov;179(11):2272-2276.
\item
  Kang Z, Zhang S, He L, Zhu H, Wang Z, Yan H, Huang Y, Dang R, Lei C,
  Chen H, Qu L, Lan X, Pan C. A 14-bp functional deletion within the
  CMTM2 gene is significantly associated with litter size in goat.
  Theriogenology. 2019 Nov;139:49-57.
\item
  Kwon, J.-W.; Kim, N.-H.; Choi, I. Expression of porcine CXADR and its
  role in blastocyst formation. In Proceedings of Society for
  Reproduction and Fertility Annual Conference 2015.
\item
  Li H, Xu H, Akhatayeva Z, Liu H, Lin C, Han X, Lu X, Lan X, Zhang Q,
  Pan C. Novel indel variations of the sheep FecB gene and their effects
  on litter size. Gene. 2021 Jan 30;767:145176.
\item
  Li H, Wang X, Chen H, Qu L, Lan X. A 17-bp InDel (rs668420586) within
  goat CHCHD7 gene located in growth-related QTL affecting body
  measurement traits. 3 Biotech. 2020 Oct;10(10):441.
\item
  Liu, Y; Ju, Z; Jiang, Q; Liu, W; Yang, C; Zhang, Y; Wang, X; Gao, Y;
  Wei, X; Sun, Y. DNA methylation and alternative splicing modulate
  FBXW11 gene expression in Holstein bull testis and are correlated with
  sperm quality. Biocell 2021, \emph{45(1)} , 79--87.
\item
  Legerlotz K, Smith HK. Role of MyoD in denervated, disused, and
  exercised muscle. Muscle Nerve. 2008 Sep;38(3):1087-1100.
\item
  Lavery GG, Walker EA, Turan N, Rogoff D, Ryder JW, Shelton JM,
  Richardson JA, Falciani F, White PC, Stewart PM, Parker KL, McMillan
  DR. Deletion of hexose-6-phosphate dehydrogenase activates the
  unfolded protein response pathway and induces skeletal myopathy. J
  Biol Chem. 2008 Mar 28;283(13):8453-8461.
\item
  Matson CK, Murphy MW, Sarver AL, Griswold MD, Bardwell VJ, Zarkower D.
  DMRT1 prevents female reprogramming in the postnatal mammalian testis.
  Nature. 2011 Jul 20;476(7358):101-4.
\item
  Matsumoto Y, Noguchi E, Imoto Y, Nanatsue K, Takeshita K, Shibasaki M,
  Arinami T, Fujieda S. Upregulation of IL17RB during natural allergen
  exposure in patients with seasonal allergic rhinitis. Allergol Int.
  2011 Mar;60(1):87-92.
\item
  Mukherjee S, Shaikh N, Khavale S, Shinde G, Meherji P, Shah N, Maitra
  A. Genetic variation in exon 17 of INSR is associated with insulin
  resistance and hyperandrogenemia among lean Indian women with
  polycystic ovary syndrome. Eur J Endocrinol. 2009 May;160(5):855-862.
\item
  Mathew SJ, Hansen JM, Merrell AJ, Murphy MM, Lawson JA, Hutcheson DA,
  Hansen MS, Angus-Hill M, Kardon G. Connective tissue fibroblasts and
  Tcf4 regulate myogenesis. Development. 2011 Jan;138(2):371-84.
\item
  Masliah E, Mallory M, Ge N, Alford M, Veinbergs I, Roses AD.
  Neurodegeneration in the central nervous system of apoE-deficient
  mice. Exp Neurol.1995 Dec;136(2):107-122.
\item
  Nemajerova A, Moll UM. Tissue-specific roles of p73 in development and
  homeostasis. J Cell Sci. 2019 Oct 3;132(19):jcs233338.
\item
  Nakashima Y, Raines EW, Plump AS, Breslow JL, Ross R. Upregulation of
  VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in
  the ApoE-deficient mouse. Arterioscler Thromb Vasc Biol. 1998
  May;18(5):842-851.
\item
  Okamoto H, Obici S, Accili D, Rossetti L. Restoration of liver insulin
  signaling in Insr knockout mice fails to normalize hepatic insulin
  action. J Clin Invest. 2005 May;115(5):1314-22.
\item
  Oh E, Spurlin BA, Pessin JE, Thurmond DC. Munc18c heterozygous
  knockout mice display increased susceptibility for severe glucose
  intolerance. Diabetes. 2005 Mar;54(3):638-47.
\item
  Pozarska A, Niess G, Seeger W, Morty, R. A role for the accessory type
  III transforming growth factor \selectlanguage{greek}β \selectlanguage{english}receptor (Tgfbr3) in lung
  alveolarisation. Eur Respiratory Soc: 2016.
\item
  Raymond CS, Murphy MW, O'Sullivan MG, Bardwell VJ, Zarkower D. Dmrt1,
  a gene related to worm and fly sexual regulators, is required for
  mammalian testis differentiation. Genes Dev. 2000 Oct
  15;14(20):2587-95.
\item
  Russell, D.W.; Wilson, J.D. Steroid 5 alpha-reductase: two genes/two
  enzymes. Annu Rev Biochem 1994, 63, 25-61.
\item
  Ruskin R, Kiet T, Amanam I, Chen L, Brooks R, Ueda S, Kapp D, Chan J.
  Differences in tumor immune regulation between African--American and
  Caucasian ovarian cancer patients. Gynecologic Oncology 2012, 127,
  S14.
\item
  Reaven, G. Insulin resistance, the insulin resistance syndrome, and
  cardiovascular disease. Panminerva medica 2005, 47, 201-210.
\item
  Ramnarine TJS, Glaser-Schmitt A, Catal\selectlanguage{ngerman}án A, Parsch J.Population
  Genetic and Functional Analysis of a cis-Regulatory Polymorphism in
  the Drosophila melanogaster Metallothionein A gene. Genes (Basel).
  2019 Feb 14;10(2):147.
\item
  StieweT, Pützer,B.M. p73 in apoptosis. Apoptosis 2001, 6,447-452.
\item
  Santos Guasch GL, Beeler JS, Marshall CB, Shaver TM, Sheng Q, Johnson
  KN, Boyd KL, Venters BJ, Cook RS, Pietenpol JA. p73 Is Required for
  Ovarian Follicle Development and Regulates a Gene Network Involved in
  Cell-to-Cell Adhesion. iScience. 2018 Oct 26;8:236-249.
\item
  Serra N, Velte EK, Niedenberger BA, Kirsanov O, Geyer CB. The mTORC1
  component RPTOR is required for maintenance of the foundational
  spermatogonial stem cell pool in mice\selectlanguage{english}+. Biol Reprod. 2019 Feb
  1;100(2):429-439.
\item
  Silveira LF, Stewart PM, Thomas M, Clark DA, Bouloux PM, MacColl GS.
  Novel homozygous splice acceptor site GnRH receptor (GnRHR) mutation:
  human GnRHR ''knockout''. J Clin Endocrinol Metab. 2002
  Jun;87(6):2973-7.
\item
  Taylor CM, Kamphuis LG, Zhang W, Garg G, Berger JD,
  Mousavi-Derazmahalleh M, Bayer PE, Edwards D, Singh KB, Cowling WA,
  Nelson MN. INDEL variation in the regulatory region of the major
  flowering time gene LanFTc1 is associated with vernalization response
  and flowering time in narrow-leafed lupin (Lupinus angustifolius L.).
  Plant Cell Environ. 2019 Jan;42(1):174-187.
\item
  Wang K, Yan H, Xu H, Yang Q, Zhang S, Pan C, Chen H, Zhu H, Liu J, Qu
  L, Lan X. A novel indel within goat casein alpha S1 gene is
  significantly associated with litter size. Gene. 2018 Sep
  10;671:161-169.
\item
  Wu M, Zhao H, Tang X, Li Q, Yi X, Liu S, Sun X. Novel InDels of GHR,
  GHRH, GHRHR and Their Association with Growth Traits in Seven Chinese
  Sheep Breeds. Animals (Basel). 2020 Oct 15;10(10):1883.
\item
  Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic
  variants from high-throughput sequencing data. Nucleic Acids Res. 2010
  Sep;38(16):e164.
\item
  Wang S, Liu S, Yuan T, Sun X. Genetic effects of FTO gene
  insertion/deletion (InDel) on fat-tail measurements and growth traits
  in Tong sheep. Anim Biotechnol. 2021 Apr;32(2):229-239.
\item
  Wang Z, Zhang X, Jiang E, Yan H, Zhu H, Chen H, Liu J, Qu L, Pan C,
  Lan X. InDels within caprine IGF2BP1 intron 2 and the 3'-untranslated
  regions are associated with goat growth traits. Anim Genet. 2020
  Feb;51(1):117-121.
\item
  Wu W, Zhang W, Choi M, Zhao J, Gao P, Xue M, Singer HA, Jourd'heuil D,
  Long X. Vascular smooth muscle-MAPK14 is required for neointimal
  hyperplasia by suppressing VSMC differentiation and inducing
  proliferation and inflammation. Redox Biol. 2019 Apr;22:101137.
\item
  Wissing ER, Boyer JG, Kwong JQ, Sargent MA, Karch J, McNally EM, Otsu
  K, Molkentin JD. P38\selectlanguage{greek}α \selectlanguage{english}MAPK underlies muscular dystrophy and myofiber
  death through a Bax-dependent mechanism. Hum Mol Genet. 2014 Oct
  15;23(20):5452-63.
\item
  Xu Y, Shi T, Zhou Y, Liu M, Klaus S, Lan X, Lei C, Chen H. A novel
  PAX7 10-bp indel variant modulates promoter activity, gene expression
  and contributes to different phenotypes of Chinese cattle. Sci Rep.
  2018 Jan 29;8(1):1724.
\item
  Yang W, Tang K, Zhang C, Xu D, Wen Q. Yang, L. Polymorphism of the
  GnRHR gene and its association with litter size in Boer goats. South
  African Journal of Animal Science 2011, 41, 398-402.
\item
  Zhou Z, Huang B, Lai Z, Li S, Wu F, Qu K, Jia Y, Hou J, Liu J, Lei C,
  Dang R. The Distribution Characteristics of a 19-bp Indel of the PLAG1
  Gene in Chinese Cattle. Animals (Basel). 2019 Dec 4;9(12):1082.
\item
  Zhang Q, Jin Y, Jiang F, Cheng H, Wang Y, Lan X, Song E. Relationship
  between an indel mutation within the SIRT4 gene and growth traits in
  Chinese cattle. Anim Biotechnol. 2019 Oct;30(4):352-357.
\item
  Zeng L, Fan X, Wang X, Deng H, Zhang K, Zhang X, He S, Li N, Han Q,
  Liu Z. Bioinformatics Analysis based on Multiple Databases Identifies
  Hub Genes Associated with Hepatocellular Carcinoma. Curr Genomics.
  2019 Aug;20(5):349-361.
\item
  Zhang W, Yang M, Wang Y, Wu X, Zhang X, Ding Y, Yin Z. Genomic
  analysis reveals selection signatures of the Wannan Black pig during
  domestication and breeding. Asian-Australas J Anim Sci. 2020
  May;33(5):712-721.
\item
  Zhang Y, Wang K, Liu J, Zhu H, Qu L, Chen H, Lan X, Pan C, Song X. An
  11-bp Indel Polymorphism within the CSN1S1 Gene Is Associated with
  Milk Performance and Body Measurement Traits in Chinese Goats. Animals
  (Basel). 2019 Dec 11;9(12):1114.
\item
  Zhao H, He S, Wang S, Zhu Y, Xu H, Luo R, Lan X, Cai Y, Sun X. Two New
  Insertion/Deletion Variants of the PITX2 Gene and their Effects on
  Growth Traits in Sheep. Anim Biotechnol. 2018;29(4):276-282.
\item
  Zhang YL, Zhong X, Gjoka Z, Li Y, Stochaj W, Stahl M, Kriz R, Tobin
  JF, Erbe D, Suri V. H6PDH interacts directly with 11beta-HSD1:
  implications for determining the directionality of glucocorticoid
  catalysis. Arch Biochem Biophys. 2009 Mar 1;483(1):45-54.
\end{enumerate}

\textbf{Figure legends}

Figure1. Information for annotation distribution of 1,122,858 InDels
from 46 Australian Boer goats and 81 local goats' genome in the present
study.

Figure 2. Genome-wide scan for a positively selected chromosome SNP in
Boer goats using pairwise fixation index (F\textsubscript{ST}) based on
InDel data. A dashed horizontal line indicates the cut-off threshold
(F\textsubscript{ST}[?]0.623043).

Figure 3. Information for top 20 Gene Ontology (GO) terms with
significant enrichment of candidate genes based on InDel data of 127
goats' genome in the present study.

Figure 4. Information for top 20 Kyoto Encyclopedia of Genes and Genomes
(KEGG) pathways with significant enrichment of candidate genes based on
InDel data of 127 goats' genome in the present study.

\textbf{Supporting information}

Table S1. Basic information and data reads-depth of 127 individuals.

Table S2. The top 1\% threshold of Fst statistical parameters based on
InDels of 127 goat individuals.

Table S3. The list of 1143 candidate genes Gene Ontology (GO) terms with
significant enrichment based on top 1\% Fst statistical parameters of
127 goats' genome.

Table S4. Information for Gene Ontology (GO) terms with significant
enrichment of candidate genes based on top 1\% Fst statistical
parameters of 127 goats' genome.

Table S5. The list of 94 candidate genes related to muscle development
by Gene Ontology (GO).

Table S6. Information for Gene Ontology (GO) terms with significant
enrichment of candidate genes related to muscle development based on top
1\% Fst statistical parameters of 127 goats' genome.

Table S7. Information for the list of 476 candidate genes with Kyoto
Encyclopedia of Genes and Genomes (KEGG) pathways with significant
enrichment of based on top 1\% Fst statistical parameters of 127 goats'
genome.

Table S8. Information for Kyoto Encyclopedia of Genes and Genomes (KEGG)
pathways with significant enrichment of candidate genes based on top 1\%
Fst statistical parameters of 127 goats' genome.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3/Figure-3}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-4/Figure-4}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

