Modern human populations are known to contain &#x22;ancient haplotypes&#x22; that originated from archaic humans by hybridization.  Some of them had been reported before the development of human genomic diversity databases, such as HapMap.  Consequently, some of them have no information about linkage disequilibrium (LD) regions.  Because genetic information within LD is tightly linked, to know LD region containing ancient haplotypes will be useful to estimate basic parameters of admixture events, and to infer biological functions that linked with the ancient haplotypes.  One of these ancient haplotypes, haplotype X (_hX_) was found in a 10.1 kb-region located on Xp11.22, which diverged at 1.4 M years ago, with low diversity within the cluster in gene genealogy and worldwide distribution in low frequency.  We determined the LD region around the ancient haplotypes using LD information obtained in the HapMap project.  The LD determination presents that the LD region surrounding the _hX_ is stable and contains genic regions that may associate with neural and brain functions

Makoto Shimada

Tsutomu Kanasashi

English

Nature Precedings

Nature Precedings December 2011
Determination of  linkage disequilibrium region suggests 
association  of  the  ancient  haplotype,  hX with  neural 
function
Makoto K. Shimada* and Tsutomu Kanasashi
Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-
1192, Japan
*Corresponding author: mshimada@fujita-hu.ac.jp
Abstract
Modern human populations are known to contain “ancient haplotypes” that originated 
from  archaic  humans  by  hybridization.   Some of  them  had  been  reported  before 
development of human genomic diversity databases, such as HapMap.  Consequently, 
some of them have no information about linkage disequilibrium (LD) regions.  Because 
genetic information within LD is tightly linked, to know LD region containing ancient 
haplotypes will be useful to estimate basic parameters of admixture events, and to infer 
biological  functions  that  linked  with  the ancient  haplotypes.   One  of  these  ancient 
haplotypes, haplotype X (hX) was found in a 10.1 kb-region located on Xp11.22, which 
diverged at 1.4 M years ago, with low diversity within the cluster in gene genealogy and 
worldwide distribution  in  low frequency.   We determined the LD region around the 
ancient  haplotypes using LD information obtained in  the HapMap project.   The LD 
determination presents that the LD region surrounding the  hX is stable and contain 
genic region that may associate with neural and brain functions. 
Introduction
Recent  advancement  of  genome-wide 
genotyping  projects  on  worldwide  human 
populations has unveiled genetic differences 
among current human populations  [1-3].  In 
the  research  history  of  human  evolution, 
some  researchers  suggested  haplotypes 
(ancient  haplotypes)  that  have  been 
considered  to  be  brought  into  anatomically 
modern  humans  (Homo  sapiens,  AMH) 
before  completion  of  these  genome-wide 
human diversity  projects  [4-9].   Under  this 
situation, genotyping of archaic human using 
paleontological  samples  revealed 
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December 2011 Nature Precedings
introgression to AMH from archaic humans 
that  occurred  more  significantly  in  non-
Africa than in Africa [10, 11].  
Because  ancestral  haplotypes  in  current 
human  populations  can  be  examined 
repeatedly  in  laboratories,  ancestral 
haplotypes will be useful maker that make up 
disadvantage  of  genome-wide  sequencing 
using paleontological samples.  
Since  information  on  some  of  ancient 
haplotypes is remain to be a piecemeal basis, 
information  of  linkage  disequilibrium  (LD) 
regions  containing  ancient  haplotypes  have 
not  investigated.   Genetic  signals  coded 
within  LD region  tightly  linked  each  other 
and are subjected to selection pressures as a 
unit.   To  determine  LD  region  of  ancient 
haplotypes is an initial step to take advantage 
of  ancient  haplotypes,  which  will  lead  to 
estimation of basic parameters of admixture 
events and assumption of biological functions 
that linked with the ancient haplotypes.   
Using HapMap information,  we  determined 
the  LD  region  surrounding  the  ancient 
haplotype,  hX.  We present here that the LD 
region surrounding the  hX shows stable LD 
region and it  contain genic region that may 
associate with neural and brain functions. 
Materials and methods
Ancient Haplotype Candidate Regions
The  hX region is  the  ancient  haplotype  we 
have reported earlier [5].  We have found the 
hX,  when  we  performed  re-sequencing  of 
10.1-kbp noncoding region in the human X 
chromosome  using  the  males  of  HGDP-
CEPH Human Genome Diversity Panel (672 
individuals  from 52 populations)  [12].   We 
observed that the hX was distributed over the 
world  at  low  frequencies.   Microsatellite 
(short tandem repeat,  STR) variation within 
the  re-sequenced  region  was  low  among 
copies of hX, even though the estimated time 
of  ancestry of  hX and other  sequences  was 
1.44 M years.  The region we performed re-
sequencing  was  selected  from  regions 
showing  low  recombination  in  human 
chromosome X by searching  recombination 
data at the time.  Furthermore, we designed 
that the regions should contain one or more 
STR sites for gene genealogical analysis.
LD determination using HapMap data
HapMap LD Data was downloaded through 
the  HapMap  Browser  (http://hapmap.org/ 
[13]) (Release #27 merged II+III, Feb 2009, 
on NCBI B36 and dbSNP b126) in JPT and 
CEU  populations.   We  defined  LD  region 
when  r2 values  of  neighboring  four 
combinations  formed  by  four  SNPs  (i.e., 
neighboring two SNPs from 5’ ends and two 
SNPs from 3’ ends) that covered the widest 
chromosomal region overlapping the ancient 
haplotype candidate region.  If the data from 
two populations (i.e.,  JPT and CEU) shows 
different region, we defined the longer one as 
the LD region.  
Results
LD region determination
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Figure 1.  LD region shown by HapMap Browser.  The  hX region is represented by grey 
area.
Nature Precedings December 2011
Based on our criteria, HapMap data in CEU 
population  showed  distinct  high-LD  SNP 
combinations over the  hX region (Figure 1). 
Table 1 shows  r2 values of neighboring four 
combinations formed by four SNPs those are 
neighboring  two SNPs  in  both  ends  of  the 
obtained LD region.  The obtained LD region 
covers  from  50,566,211  to  50,621,379  in 
NCBI B36, which spans 55,169 bp in length. 
Comparing the length of LD region with that 
of the  hX region (50,583,087 to 50,593,170, 
10,084 bp in length), the LD region extends 
to 5.47 times of the hX region in length.  
Page 3 of 7
Table 1. HapMap LD data representing LD region of hX
pos_SNP1 pos_SNP2 pop rsID_SNP1 rsID_SNP2 D' r 2 LOD
50,566,211 50,619,102 CEU rs5915314 rs5915333 1 0.851 17.61
50,566,211 50,621,379 CEU rs5915314 rs2382650 1 0.851 17.61
50,571,456 50,619,102 CEU rs6614576 rs5915333 1 0.898 18.56
50,571,456 50,621,379 CEU rs6614576 rs2382650 1 0.898 18.56
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Figure 2.  Genomic annotation of the LD region containing  hX shown by UCSC genome 
browser.  The hX region is represented by black bar with red gaps at the top of the view.
December 2011 Nature Precedings
Observation of hX LD region
Figure 2 shows annotations on the obtained 
LD  region  in  the  UCSC  genome  browser 
[14].  According to the annotation shown in 
the  UCSC genome browser,  the  LD region 
contains  the  first  exon  and  intron  of 
SHROOM4  gene,  and  its  promoter  and/or 
enhancer, those are not included in the 10.1-
kb  hX region.   SHROOM4  is  thought  to 
regulate  cytoskeletal  architecture  by 
modulating the spatial distribution of myosin 
II  [15].   SHROOM4  gene  is  expressed 
various types of cells.  It is noteworthy that 
SHROOM4 gene functioned in  neurulation, 
which is based on the fact  that SHROOM4 
gene is related to the Stocco dos Santos X-
linked  mental  retardation  syndrome. 
Furthermore,  the  annotation  of  OMIM  [16] 
data indicates that the LD region is associated 
with mental  disorders  suggested by at  least 
17 studies.  
Discussion
We present that LD region containing the hX 
also contain functional regions that related to 
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Nature Precedings December 2011
brain  and/or  central  nerve  system  (CNS), 
though  hX region itself is noncoding region. 
Because strong LD region inherits as a block, 
LD region act as a genomic regional unit in 
evolution.   The variation on the LD region 
containing  ancient  haplotype  may  represent 
ancient  variation.   Using  knowledge  of 
relationship between sequence variation and 
function,  the  LD  region  may  be  used  to 
predict functional difference between archaic 
human  and  majority  of  AMH.   Moreover, 
because evolution of brain/CNS is significant 
to  human  evolution,  the  maintenance 
mechanism  of  ancestral  haplotype  in 
introgression process may be a clue to solve 
brain/CNS evolution in human lineage.  The 
some  other  ancient  haplotypes  suggesting 
introgression  from  archaic  human  to  AMH 
have association with brain/CNS phenotypes, 
such as the H2 haplotype on the MAPT gene 
locus  [8,  9] and  the  D  haplotype  of  the 
microcephalin (MCPH1)[7].  These examples 
may encourage developing a hypothesis that 
introgression  from  archaic  human  have  a 
certain  role  in  human  evolution.   The  LD 
region obtained in the present study will be 
expected  to  help  researchers  in  further 
studies. 
Acknowledgements
We are grateful  to Michiyo Murase for her 
help in the analysis.  This work is based on 
the  study M.K.S performed with  Jody Hey 
and his colleagues, and financially supported 
by  Grant-in-Aid  for  Scientific  Research  on 
Innovative Areas (22101001).
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Determination of linkage disequilibrium region suggests association of the ancient haplotype, hX with neural function

http://precedings.nature.com/documents/6737/version/1

Determination of linkage disequilibrium region suggests association of the ancient haplotype, hX with neural function

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