humna meiomap

7/23/2019 Humna MeioMap

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Guo CHENG, Pos

Nature Genetics 47, 727–735 (20



The cause of the extra or missing chromosomeproblem

Nora!"uan #od$ce!! %i&!oid

%o'n $ndroeAneuploid

Aneuploidy is the presence of an abnormal number of chromosomes in a cell, such as ha

chromosomes when 46 is expected.



Gaete"a&!oid

Meiosis

arent %i&!oid

Maleandfemalegametes uniteinfertilization

Homoloro t+e

Meiosis in reproduction



arent %i&!oid

Maleandfemalegametes uniteinfertilization

Meiosiserror

Gaete-neu&!oid

Meiosis error causes aneuploidy

o&u!ation#ased stud$ ana!$e t+e inoration o t+e eiosisend &roduct



The limitations of population-basedanalyses

Neg!ected in utero se!ection on aneu&!oid$ *aused #iases in t+e estiation o aneu&!oid$ incidence, interc+roosoe susce&ti#i!it$ dierence, etc.

*annot direct!$ identi$ t+e origin o c+roosoe segregation errors issing data &ro#!e data inter&retation aries de&ends on dieo#ecties o studies



Objective of the study: MeioMap! for eachfemale meiosis

eioa&: sing!ece!! #ased ana!$sist+at o!!o' t+e eiosis &rocess as or+o' c+roosoes segregate

ea!e eiosis as t+e su#ect ostud$

a& t+e crossoers #et'een+oo!ogue c+roosoes



"emale meiosis error as the major cause ofaneuploidy

Nagaoa 9, et a!. Nature eie's Genetics 13,



des of arrest of the female meiosis process

Nagaoa 9, et a!. Nature eie's Geneticsdoi:10.1038/nrg3245

>+e ore adanced is t+e ea!e age, t+e !ong 'ou!d t+e %ict$ate arrest stand+oo!ogue &airing deteriorates



ister c+roatids co+esion ensure t+e &airing or

eiosis 99

?ose &airing o t+e+oo!ogue

c+roosoe



$ole of crossovers in chromatid cohesion

*orrect *rossoersensure +oo!og

&airing

*rossoers too ar rocentroere oreco#ination ai!ure(0) causes is

segregation *rossoers too c!ose to

centroere causes nondisunction o+oo!ogues or&reature se&arationo sister c+roatids

Nagaoa 9, et a!. Nature eie's Genetics 1

or

riar$ooc$te

eiosi9



An ideal MeioMap! for each female m

- a& o c+roatid i - a& o crossoer a

reco#ination eent - eiosis &rocess as

&ossi#!e



%ummary on info of the participants and studysubjective

u#ects re&resent ea!es 'it+ adanced re&roductie age (-@G A3

-!! su#ects +ad under'ent oarian stiu!ation and ooc$te actiationooc$teB trios)

>+e e#r$oB trio donor (nC1, in tota! ; trios) +ad recurrent iscar#eore t+e in itro erti!iation (9@) c!inic

or t+e ooc$teB trio donors (nC5, in tota! 13 trios), no indication onaterna! genetics actor, eDce&t or adanced age



Map the chromosomes

&hole genomeampli'cationof the Trios

#(A

)enotyping*hasing:

connect thedots of

genotypealleles



%N- a&!es: Bod$ ce!!s (#ucca! s'a#) %N- E B trios %N-

or B trios, &rior to genot$&ing: sing!e ce!! %N- eDtraction (ce!! !$sis)

'+o!e genoe a&!iFcation

N #ead arra$ genoe'ide genot$&ing, 300,000 Ns (sing!e nu

&o!$or&+iss) as road a& o t+e genoe and aneu&!oid$ detectio

- second &!ator (a*G", arra$ co&aratie genoic +$#ridiation)

aneu&!oid$ Fndings

)enotyping:



*hasing:



MeioMap! of each single meiosis

oocyte



$esults: the main 'ndings

- ne', reerse segregation &attern in +uan eiosis

G!o#a! reco#ination rates as a ris actor or aneu&!oid$

eiotic drie or reco#inant c+roatids at eiosis 99



"inding +,: A ne. chromosomesegregation pattern

Handers I, a!i ", *urr Bio!. @o!ue 25, 9ssu-ugust 2015



$everse Meiosis: /01 .ere follo.ed .ith mei22 errors



"inding +/: $ecombinant chromatids are t.icli3ely to segregate to the oocyte



$ecombination pragainst aneuploid

essage #$ Fnding (2) and (3):



%ummary

- ne', reerse segregation &attern eDists in

+uan eiosis and is error&rone or eiosis 99(23J) additiona! origins o aneu&!oid$

G!o#a! reco#ination rates &rotects agaistaneu&!oid$

eco#inant c+roatids are t'ice !ie!$ to&ass do'n to t+eooc$tes, i.e. t+e neDt generation, at eiosis 99

&ositie se!ection or reco#inant c+roatids



4thical 5 6egal considerations: eD&erients ogenoe o "uan e#r$osK



*itfalls

L#serations 'ere under t+e inMuence o ->, e.g. t+e ostiu!ation and ooc$te actiation

incidence o aneu&!oid$ +as #een &roed to #e diereco&ared 'it+ natura! c$c!es

9ntererence o '+o!e genoe a&!iFcation on aneu&!oid$detection and &+asing

9n case o aneu&!oid$, t+e &+asing a!gorit+ 'ou!d #e ae

Ga&s sti!! eDist #et'een inerence and inter&retation o t+eioa&



%igni'cance of the 'ndings

2mpacts: t+ree +ig+i&act coent artic!es o!!o'ing its

&u#!ication c+anged t+e doga on ea!e eiosis and genetic

eo!ution



&as Human meiosis brea3ing! orbending! the rules

eerse eiosis: error or norK IDact cause is sti!! unno'n *ou!d #e agere!ated, or re!ated to t+e crossoer near cen

region

eiotic drie versus ?a' o ende!ian in+eritance

trong se!ection or reco#inant c+roatids versus randoreco#ination

humna meiomap

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