We are going to talk about a similar - -We are going to talk about

By Maurice Rivera,2014-05-27 19:02
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We are going to talk about a similar - -We are going to talk about

    Meiosis, featuring Dr. Wendy Chung

    Meiosis basics:

    ; We are going to talk about a similar process to mitosis, but rather than forming two

    sister cells with the same genetic material, we will discuss a rather different case in


    ; Why bother having sexual reproduction, evolutionarily? Why don’t we clone


    ; Although we may think we’re perfect, we probably aren’t, and we need to adapt over


    ; 2000 years ago, those of us who wear glasses wouldn’t have survived, and those of us

    who store energy efficiently and tend to gain weight, aren’t surviving as well in this

    environment as we did in other environments

    ; In sexual reproduction, we shuffle our genomes- mix and match to invent

    advantageous or detrimental new combinations

    ; Having a variety of children with different genetic makeups increases the chances

    that one will be successful in his or her environment

    How to make new, interesting genomes:

    ; We have two distinct lineages in our body

    ; Somatic cells (from reproductive view, these only exist to support... ; germ cells (eggs, sperm)

    ; How do we get from germ cells to haploid cells in eggs or sperm?

    ; And thus back to diploid organism

    ; How do you go from diploid (2n = two genome’s worth of information) to 1n (one

    genome)- key question

    ; many mechanisms are the same as in mitosis (same stages, prophase, metaphase, etc.) ; From germline we get somatic and germ cells eventually

    ; Everything lines up on metaphase plate and the cells and chromosomes divide

    elegantly with complex cellular machinery and all of the things applicable to mitosis

    are applicable to meiosis

    ; What’s different is that we go through 2 rounds of cell division

    ; In first round, we duplicate the 2n genome to 4n, then divide to 2n ; In second round, we divide to haploid (or 1n) genome at end of process ; You recall from mitosis that those sister chromatids are lining up on the metaphase

    plate, and the sister chromatid are each separating, so that each of the daughter cells

    has the same genetic compliment as the mother cell

    ; In the first meiotic division, we separate homologous chromosomes, each of which

    are composed of sister chromatid, and each chromatid has approximately the same

    genetic material as its sister, but the daughter cells are incredibly different from each


    ; Then the subsequent divisions go to the haploid genome

    ; One chromosome from a father, one from a mother, then duplicate genetic material

    on each of the chromosomes (sister chromatid for the mother’s copy, sister

    chromatid for the father’s copy)

    ; Those maternal and paternal homologous chromosomes line up, and in the first

    meiotic division, those maternal and paternal homologous chromosomes separate ; In the daughter chromosomes you still have a pair of sister chromatid (one from the

    paternal line here, one from the maternal line here,) and in the second round of

    meiotic cell divisions, you get a division of the sister chromatid ; By the end of the entire process, you started with one cell and produced four cells,

    and gone from 2n to 1n genetic material

    ; Even though paternal chromosome starts out completely red and the maternal

    chromosome starts out completely black, you’ll notice that the chromosomes down

    at the bottom aren’t all black or all red

    Molecular basis of recombination:

    ; During this process- there is recombination, exchange between sister chromatid ; You do not pass down complete chromosomes for this reason

    ; Prophase of first cell division of meiosis

    ; Chromosomes are separated at centromere

    ; Homologous chromosomes line up at centromere, then crossover recombination is

    possible (exchange of genetic information)

    ; Form chiasms

    ; Important when we consider chromosome separation in females- the chiasmata keep

    all four homologous chromosomes together so that they stay as one structure ; Without chiasmata as glue, they could drift apart and not separate evenly- related to


    ; All of this happens in Meiosis I (chiasmata form, on average each chromosome has

    2-3 recombination events)

    ; At Anaphase 1, recombinations are complete, breaks are made, and shuffling of

    genetic information remains

    ; Result is two sets of slightly different chromosomes

    ; Second meiotic division is separation of chromatid pairs into haploid cells ; To review, we go from diploid to haploid, and then genetic material in each gamete

    is different than the parent chromosomes

    ; Recall that this happens for 23 chromosome pairs, and they all assort independently ; Combinatorial possibilities = 2^23, in addition to recombination events- amazing

    amount of variability produced by sexual reproduction

    How Long Does Meiosis Take?

    This is long, sorry...

    When in life does this take place?

    ; For men- this basically happens in puberty. From embryogenesis the spermatid and

    precursors of sperm remain diploid. In puberty, gametogenesis begins, and doesn’t


    ; If seen in a baby, the baby is a mosaic; a composition of two different cell lines, one

    of which is normal and the other is triploid- associated with birth defects and mental


    ; Somewhat more common in fetal demise or miscarriage

    How common is this?

    ; How often do we make mistakes? For men, this happens in your sperm about 8% of

    the time, regardless of age. For women, we make mistakes an average of 20-30% of

    the time, and this increases as we get older.

    ; If we look at pre-implantation embryos, even the “good” embryos have problems

    30-40% of the time. “Bad” embryos have problems around 80% of the time

    ; Very early miscarriages/ early recognized pregnancies- over half of them are due to

    chromosomal problems

    ; Later in gestation, the percentage is around 10%

    ; By the time you get to liveborn births, fewer and fewer survive.

    ; I didn’t graph this because it will depress you. As you get older, the odds increase

    that your egg will have a chromosome problem. This chart shows that the odds are

    low at 30 (1/1000 Downs, 1/500 some chromosomal abnormality)

    ; at 40-45, numbers get much higher

    ; If we look at which parent caused the chromosomal problem, with the exception of

    XXY (Klinefelter’s), the problem came from the woman’s side

     Most trisomies are inviable; you will occasionally see 13, 18 (with bad problems,) 21, ;

    and extra X or Y (which are pretty resilient)

    ; This is because the least gene dense chromosome is 21. 13 and 18 are second and

    third in terms of least amount of genetic material, although their trisomies are

    incredibly mentally retarded and usually don’t live very long.

    ; Chromosome 16 trisomies are inviable but it seems to happen all the time, for some

    damn reason

    Trisomy Rescue (or, “uniparental disomy”)

    ; There is an unusual situation in which this problem can resolve; you can go from an

    extra chromosome to a normal situation. Called “trisomy rescue,” and it is due to an

    error in mitosis

    ; Reduces down to 46 chromosomes and develops normally

    ; Question becomes, which of your three chromosomes do you lose? If you start with

    two copies of your mom’s chromosome and one of your dad’s, you can lose any of

    them. If you lose a copy of your mom’s chromosome, you’re in great shape. If you

    lose your dad’s, you’re still probably ok, but there are a few situations in which this

    can come to light:

    ; if child ends up with autosomal recessive mutation, and only one parent was a carrier,

    then you have probably gone from a trisomy situation with a rescue that reduced ; Also, not all maternal genes are exactly the same as all paternal genes. In a process

    called imprinting, it is marked which gene came from your mom, and which came

    from your dad

    ; One copy may be silenced by methylation, and thus not expressed, and then it very

    much matters whether you got it from mom or dad

    ; If mom’s copy was imprinted/silenced, and you happen to have two of her copies,

    then you have no functional copy of that gene. In this situation, “uniparental

    disomy” is very important. Angelmann’s Syndrome results from this.

    Aneuploidy in the Sex Chromosomes

    ; Most common aneuploidy is in sex chromosomes. Having one too few sex

    chromosomes is worse than having one too few

    ; One missing X chromosome is “Turner’s syndrome” Its karyotype is 45,X. Of all of

    Turner’s from conception, 99% will not make it to birth. But that 1% survives

    ; Problems with fertility, short stature

    ; Too many X or Y chromosomes is more subtle, and you could go your entire life

    without knowing you have a problem until you want to have children ; Y chromosomes are very small and contain little information

    ; X chromosomes, in lionization process, are randomly inactivated, and become Barr

    bodies which are never expressed

    Gene Mapping Strategies

    ; FISH: fluorescent in-situ hybridization can tell you whether a specific sequence is

    missing or duplicated- very easy to see

    ; Recombination probability: the likelihood of a recombination event between any two

    genes along a chromosome is proportional to the distance between those two genes ; There is a greater likelihood that you will have a crossover between two genes if they

    are far than if they are close

    ; In the old days before the human genome, we used to map genes this way

    How do these mutation mechanisms cause disease?

    ; A point mutation can cause loss of function: can mess up the active site, can cause

    premature truncation, etc. Autosomal recessive diseases usually work this way. ; Also gain-of-function mutations take place that give a protein a whole new function

    that takes on a life of its own that causes trouble

    ; In single-celled organisms, there are temperature-dependent mutations that affect

    conformation of an enzyme

    ; From a biochemical standpoint, most loss-of-function mutations are well tolerated

    with a 50% loss of enzyme activity (i.e., one functional copy of the gene) ; yet occasionally, some loss-of-function mutations are inherited dominantly ; This is the case with some cancer susceptibility genes, such as familial adenomatous


    ; Due to loss of function mutation in proteins that control cell-cycle known as “tumor

    suppressor genes”- inherited dominantly, but at the cellular level, they act recessively ; The problem happens when you get a somatic mutation in the second copy of the


    ; Haploinsufficiency: when 50% activity just don’t do it. One example is Maturity

    Onset Diabetes of Youth; the involved glucose transporter is very carefully regulated,

    and half activity just isn’t good enough.

    ; Dominant negative mutations: the bad, mutant copy could acquire a function that

    acts as a “poison pill” towards the normal copy of the gene

    ; Case of osteogenesis imperfecta; a problem in one copy of the collagen gene that

    acts as a multimer, a fibril for the connective tissue, leading to brittle bones. One bad

    copy will poison the good copies of that multimer.

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