Guo CHENG, Post-doctoral Fellow

Pediatric Surgery

Nature Genetics 47, 727735 (2015) doi:10.1038/ng.33

The cause of the extra or missing chromosome

problem

Down Syndrome
Aneuploid

Normal
Human body
cell Diploid
Aneuploidyisthepresenceofanabnormalnumberofchromosomesinacell,suchashaving45or47
chromosomeswhen46isexpected.

Meiosis in reproduction

Homologue chromosome
from the father and mother

Male
and
female
gamete
s unite
in
fertiliza
tion

Meiosi
s

Parent Diploid

Gamete
Haploid

Child Diploid

Meiosis error causes aneuploidy

Male
and
female
gamete
s unite
in
fertiliza
tion

Meiosi
s
error

Parent Diploid

Gamete
Aneuploid

Population-based study analyze the information of the Meiosis

end product

Child
Aneuploid

The limitations of population-based

analyses
Neglected in utero selection on aneuploidy
---- Caused biases in the estimation of aneuploidy incidence, inter
chromosome susceptibility difference, etc.
Cannot directly identify the origin of chromosome segregation errors
---- missing data problem; data interpretation varies depends on different
objectives of studies

Objective of the study: MeioMap for each

female meiosis

MeioMap: single-cell based analysis

that follow the meiosis process as for
how chromosomes segregate
Female meiosis as the subject of
study
Map the crossovers between
homologue chromosomes

Female meiosis error as the major cause of

aneuploidy

Nagaoka SI, et al. Nature Reviews Genetics 13, 493-504 (July 2012) |

ades of arrest of the female meiosis process

The more advanced is the female age, the long would the Dictyate arrest stands, and the
homologue pairing deteriorates
Nagaoka SI, et al. Nature Reviews Genetics 13, 493-504 (July 2012) |
doi:10.1038/nrg3245

Lose pairing of the

homologue
chromosome

Sister chromatids cohesion ensure the pairing for

Meiosis II

Role of crossovers in chromatid cohesion

Correct Crossovers
ensure homolog
pairing
Crossovers too far from
centromere or
Recombination failure
(R0) causes missegregation
Crossovers too close to
centromere causes nondisjunction of
homologues or
premature separation
of sister chromatids

Primary
oocyte

Meiosis
I

or

Nagaoka SI, et al. Nature Reviews Genetics 13, 493-504 (July 2012) |

An ideal MeioMap for each female meiosis

A Map of chromatid identity

A Map of crossover and
recombination events
A Meiosis process as natural as
possible

Summary on info of the participants and study

subjective
Subjects represent females with advanced reproductive age (AVG ~37.3 yrs)
All subjects had underwent ovarian stimulation and oocyte activation (for
oocyte-PB trios)
The embryo-PB trio donor (n=1, in total 9 trios) had recurrent miscarriage
before the in vitro fertilization (IVF) clinic
For the oocyte-PB trio donors (n=5, in total 13 trios), no indication on abnormal
maternal genetics factor, except for advanced age

Map the chromosomes

Whole genome
amplification
of the Trios
DNA

Genotyping

Phasing:
connect the
dots of
genotype
alleles

Genotyping:

DNA Samples: Body cells (buccal swab) DNA + PB trios DNA

For PB trios, prior to genotyping: single cell DNA extraction (cell lysis) followed with
whole genome amplification
SNP bead array genome-wide genotyping, > 300,000 SNPs (single nucleotide
polymorphisms) as road map of the genome and aneuploidy detection
A second platform (aCGH, array comparative genomic hybridization) to validate the
aneuploidy findings

Phasin
g:

oocyt
e

MeioMap of each single meiosis

oocy
te

Results: the main findings

A new, reverse segregation pattern in human meiosis
Global recombination rates as a risk factor for aneuploidy
Meiotic drive for recombinant chromatids at meiosis II

Finding (1): A new chromosome

segregation pattern

Zanders SE, Malik HS, Curr Biol. Volume 25, Issue 15, pR654R656, 3
August 2015

Reverse Meiosis: 23% were followed with meiosis

II errors

Finding (2): Recombinant chromatids are twice

likely to segregate to the oocyte

Recombination protects
against aneuploidy

Message by finding (2) and (3):

Summary
A new, reverse segregation pattern exists in
human meiosis and is error-prone for meiosis II
(23%)
---additional origins of aneuploidy
Global recombination rates protects agaist
aneuploidy
Recombinant chromatids are twice likely to
pass down to the
oocytes, i.e. the next generation, at meiosis II
---positive selection for recombinant chromatids

Ethical & Legal considerations: experiments on the

genome of Human embryos?

Pitfalls
Observations were under the influence of ART, e.g. the ovarian
stimulation and oocyte activation
---incidence of aneuploidy has been proved to be different
compared with natural cycles
Interference of whole genome amplification on aneuploidy
detection and phasing
In case of aneuploidy, the phasing algorithm would be affected
Gaps still exist between inference and interpretation of the
MeioMap

Significance of the findings

Impacts:
three high-impact comment articles following its
publication
changed the dogma on female meiosis and genetic
evolution

Was Human meiosis breaking or

bending the rules
Reverse meiosis: error or norm?
Exact cause is still unknown
Could be age-related, or related to the crossover near centromere
region
Meiotic drive versus Law of Mendelian inheritance
Strong selection for recombinant chromatids versus random
recombination

Discussions