Genetics

Life Sciences

3-Genetics

Posted by Yingshan Li on July 8, 2019

现代生物学开端于经典遗传学，由孟德尔开创，是生命科学的基石。事实上生命的一个最重要最基本的特征就是能够稳定地遗传，而遗传学就是研究这一重要现象背后规律的学科。孟德尔在经过1856-1863这8年的豌豆杂交试验后提出了孟德尔定律，但一直到40年后才逐渐受到人们的重视，自此开创了近代遗传学。当时的人们不知道DNA，不知道蛋白质，不知道基因，对于现代生物学的知识几乎一无所知。在这样的背景下孟德尔能够观察豌豆的遗传现象，并做长达近十年的枯燥的数豌豆试验最后归纳出孟德尔三大定律是非常伟大的！

进入近现代以来，遗传学早已不在局限于宏观的遗传现象了，1953年Watson和Crick对DNA双螺旋的发现使遗传学进入了一个新的时代，从此人们能够从分子层面来研究各种生命现象了。这一章我们就从微观到宏观来一步步解析遗传学的理论基础。

1. DNA

Nelson and Cox, Principles of BiochemistryNelson and Cox, Principles of Biochemistry

1. Deoxyribonucleotides and ribonucleotides

DNA或RNA是所有生命的遗传物质，其中只有部分病毒采用RNA作为遗传物质，所有的非病毒生物都采用DNA作为遗传物质。DNA和RNA为大分子（脱氧）核苷酸链，每个（脱氧）核苷酸都具有一个5‘磷酸基团、一个3’五碳糖、和一个碱基。

2. Phosphodiester linkages in covalent backbone

DNA或RNA链的延伸只能是从5‘到3’，因为DNA／RNA polymerase可以做用到DNA/RNA链的3‘OH基团上。The energy for polymerization come from dNTP (deoxynucleoside tri-phosphate). Thus the free dNTP needs to be hydrolyzed and attached to the free -OH which resides only in 3’. The other way around won’t be able to provide enough energy for the reaction.

3. Base pairing

A跟T配对，有两个氢健；G跟C配对，有三个氢健。为什么只能是这样的配对方式呢？Firstly, some options are ruled out because they can’t form more than 2 or 3 hydrogen bounds. However, G and T can form 2 hydrogen bonds and thus stable. G and T pairing can occur in RNA but not DNA because the DNA repair system will correct most of the Non-Watson-Crick pairing.

为什么DNA是双螺旋结构呢？碱基是疏水基团，而磷酸基是亲水基团，所以在DNA链中碱基在内部而磷酸基团在外部。DNA内部的碱基会一层一层地叠起来，再加上每个碱基的特定结构，最后DNA只有是双螺旋的时候才是最稳定的。

为什么DNA是反向互补呢？This is determined by the base parings. It’s pretty amazing that A-T and C-G paring both make the -OH expose in the opposite direction.

2. Chromosomes:

真核生物跟原核生物最大的不同点之一就是真核生物具有膜包被的细胞核，细胞核中的遗传物质被高度压缩成染色体。

Griffiths et al., An Introduction to Genetic AnalysisGriffiths et al., An Introduction to Genetic Analysis

  1. Heterochromotin: Densely compacted regions where most of the selfish elements are located, usually around centromeres.
  2. Euchromatin: Loosely compacted regions where most of the active genes are located
  3. Centromeres: The region of the chromosome where spindle fibers attach. Satellite DNA (lowly complexed repeat sequences) are usually located in the heterochromatic regions flanking centromeres.
  4. Nucleolar organizers: Nucleolus contain ribosomal RNA. Nucleolar organizers are located within nucleolus and contain the genes that code for ribosomal RNA, which are usually in tandam repeats (~200 copies) to make sure the large amount of rRNA in the cell.
  5. Tolemers: The ends of chromosomes. Usually the ends of chromosomes are hard to replicate but this problem is solved by the fact that tolemers contain tandem short DNA repeats.
  6. Histones: Histones are highly alkaline proteins that are highly conserved across eukaryotes. Histones package DNA into nucleosomes. There are fine families of histones: H2A, H2B, H3, H4 and H1/H5. H2A, H2B, H3, H4 are the core histones that form octamers (two units of each) to wrap DNA. H1/H5 are linker histones that link and further package nucleosomes. Griffiths et al., An Introduction to Genetic AnalysisGriffiths et al., An Introduction to Genetic Analysis
  7. Genome sizes: Griffiths et al., An Introduction to Genetic AnalysisGriffiths et al., An Introduction to Genetic Analysis

3. Mitosis and meiosis

Griffiths et al., An Introduction to Genetic AnalysisGriffiths et al., An Introduction to Genetic Analysis

  1. spindle fibers (microtubule): polymers of the protein called tububin.
  2. kinetochore: A disc-shaped protein complex attached to the centromeres of duplicated chromatids and the spindle fibers so to pull chromatids apart during cell division. Tubulins depolymerize at the kinetochores to shorten the spindle fibers thus to pull apart the sister chromatids.

4. Recombination

  1. Crossing-over occurs atthe four-chromotid (tetrads) stage

5. Genetcis of bacteria and bacteriaphage

Griffiths et al., An Introduction to Genetic AnalysisGriffiths et al., An Introduction to Genetic Analysis

  1. Horizontal gene transfer: Transformation, conjugation, transduction
  2. F factor: A small circular plasmid that allows cell to donate genetic material.
  3. Conjugation: F plasmid in F+ cells synthesizes pilus to make a contact with F- cells. Then the F DNA make a single-strand copy of itself by rolling circle replication mechanism to the F- cells, converting F- cells into F+ cells.
  4. Hfr strains: strains where F plamsid integrated into chromosome. This allows the transferring of genomic DNA form the donor to the recepient.
  5. Transformation:
  6. Transduction:
    1. Random transduction: Phages incorporate random host DNA fragment and transduce to other bacteria
    2. Specialized transduction: Phages insert into bacterial chromosome at specific location and only transduce DNA that are nearby. Phage lamda is a good example (mechanism not shown here).

6. From genotype to phenotype

Griffiths et al., An Introduction to Genetic AnalysisGriffiths et al., An Introduction to Genetic Analysis

  1. Epistasis: One mutation at one loucs can overide a mutation at another locus in a double mutant. This is different from dominance as dominance refers to two allels at the same gene locus.

7. Transposable elements

  1. Transposons in prokaryotes:

  2. Insertion-sequence (IS) elements in bacteria: phage lamda inserts next to the gal operon in E. coli. Several E. coli gal- mutants were found to contain large insertions of DNA into the gal operon and many different insertion mutations are caused by a small set of insertion sequences instead of ramdom sequences.

  3. Two types of bacterial transposons: composite transposons (two inverted repeats IS elements flanking a gene and IS elements encodes transposase) and simple transposons (short IR sequences flanking transposase gene and other genes) Griffiths et al., An Introduction to Genetic AnalysisGriffiths et al., An Introduction to Genetic Analysis

  4. Prokaryotic transposition from plasmid to to host: Conservative trasnposition (transposons do not replicate) and replicative transposition (transposons replicate)

  5. Transposons in eukaryotes

  6. Dr. MxClinktock’s experiment in maize: the Ds element (activated by Ac element which encodes transposase)

Griffiths et al., An Introduction to Genetic Analysis

  1. Two major types of transposons: RNA transposon (retrotransposon) and DNA transposon. Retrotransposons are predominantly abundant in eukaryotic genomes. The first transposon Ds identified from maize is a DNA transposon.

Griffiths et al., An Introduction to Genetic AnalysisGriffiths et al., An Introduction to Genetic Analysis

DNA transposons:

  1. Transposons in human

Griffiths et al., An Introduction to Genetic Analysis

Remarkebaly: a specific SINE called Alu (~200bp) has more than 1 million copies in human genome which makes up more than 10 percent of the whole genome.

Griffiths et al., An Introduction to Genetic Analysis

  1. Safe havens for successful transposons: non-coding regions, other transposons, and expecially centric heterochromotin where there are virtually devoid of genes but have many repetative sequences. Nearly 70% of yeast genome are introns but yeast genome harbors hundreds of copies of Ty elements. This is because Ty elements can insert into only specific locations in genome. For example, Ty3 elements only insert to regions near tRNA genes. R1 and R2 elements are both LINES in arthropods and only insert into rRNA gene clusters. Griffiths et al., An Introduction to Genetic Analysis

  2. Certain transposons evolved to be the essential part of host genomes: Tolemerase

Griffiths et al., An Introduction to Genetic Analysis

8. DNA repair and Recombination

Griffiths et al., An Introduction to Genetic AnalysisGriffiths et al., An Introduction to Genetic Analysis

9. Large-scale chromosome mutations

Griffiths et al., An Introduction to Genetic AnalysisGriffiths et al., An Introduction to Genetic Analysis

Variations in chromosome numbers:

  1. Monoploids: Monoploids are very rare in higher eukaryotes. Exceptions include wasps, ants and male bees. This is because monoploid zygotes or germ cells cannot go through meiosis due to the lack of pairing chromosomes, thus causing sterility. Wasps, ants and male bees produce gamets by mitosis instead of meiosis.

  2. Polyploids: Common in plants but rare in animals. Usually the higher the number of chromosome copies, the larger the size of cells or organisms.

Variations in chromosome structure:

Fates of human zygotes

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