4 分钟阅读

1. Genome

Genome is the genetic material of an organism. It consists of DNA, or RNA in RNA viruses. 具体说来，下列元素都属于 genome：

  • DNA, 包括：
    • protein-coding genes
    • pseudogenes
    • transposon (TE - transposoble element)
    • DNA elements that can “jump” to a new genomic location
  • RNA, 包括：
    • rRNA (ribosomal RNA)
    • tRNA (transfer RNA)
    • short non-coding RNA
      • miRNA (microRNA)
        • MicroRNAs usually induce gene silencing by binding to target sites found within the 3’UTR of the targeted mRNA. This interaction prevents protein production by suppressing protein synthesis and/or by initiating mRNA degradation.
        • MicroRNAs are partially complementary to one or more messenger RNA (mRNA) molecules, and their main function is to downregulate gene expression in a variety of manners, including translational repression, mRNA cleavage, and deadenylation.
      • siRNA (short interfering RNA, double-stranded)
        • may come from outside the cell (e.g. virus); endo-siRNA also discovered, transcribed from cell’s own DNA
        • the most commonly used RNA interference (RNAi) tool for inducing short-term silencing of protein coding genes
        • siRNA is a synthetic RNA duplex designed to specifically target a particular mRNA for degradation.
      • 参考：
    • lncRNA (long non-coding RNA)
      • $\ge$ 2000 nt
      • variety of functions

DNA/RNA 其实是 molecule 的名称，所以 genome 和 DNA/RNA 的关系大致相当于 “一坨炭” 和 “碳分子” 的关系

2. Chromosome / Chromatin / Nucleosome / Chromatid / DNA / Double Strands

2.1 DNA / Double Strands

DNA 是 molecule 的名字，Double Strand (or Double Helix) 是它的物理结构

DNA 由下面两类元素构成：

  • Nucleotide ([‘nju:klɪətaɪd], 核苷酸)，包括：
    • Adenine ([‘ædənɪn], 腺嘌吟)
    • Cytosine ([‘saɪtəʊsi:n], 胞嘧啶)
    • Guanine ([‘gwɑ:ni:n], 鸟嘌呤)
    • Thymine ([‘θaɪmi:n], 胸腺嘧啶)
  • Sugar-Phosphate Backbone

2.2 Chromatin / Nucleosome / Chromatid

  • DNA + histone 的 complex 整体叫做 chromotin
  • cell 在不分裂的情况下，可以认为：一条 further condensed chromatin 就是一条 chromosome
  • cell 在分裂的情况下 (具体在 Cell Cycle 的 $S$ phase)，一条 chromosome 会被复制成两条 sister chromatids
    • Every 2 sister chromatids are connected by a centromere.
    • Every chromatid has a short p-arm (“p” for “petit”) and a long q-arm (“q” for “queue”)
    • 我们在研究单条 chromosome 的时候仍然会使用 p-arm、q-arm 和 centromere 来细分单条 chromosome 的结构
    • 注意： 我们经常看到的 chromosome 的图片都是一个 X-shaped with 4 arms 的结构，这其实是分裂中的两条 chromatids，注意这并不是 chromosome 的正常形态，人体内并不是有 23 对这样的 X-shaped chromosomes (我 TM 被这个图片骗惨了！)

[!caution] Chromatin 🆚 Chromatid

chromatin 是 chromosome 的物理结构、组成部分。

chromatid 是 chromosome 在细胞增殖时的特殊形态。

它俩就不是一个维度上的概念，不需要去考虑它们的区别与联系。

2.3 Chromosome

chromosome 按功能分类可以分为:

  1. allosome ([‘ælʊsəʊm], 性染色体)
  2. autosome ([‘ɔ:təsəʊm], 常染色体)
    • 人体的 autosome 是按长度从长到短编号的，最长的是 $1$ 号，最短的是 $22$ 号

What do we mean when we say $\text{chr}_{18}$?

我们可以说 “人体每个细胞都有 a pair of $\text{chr}_{18}$’s”:

  • 我们可以用 $\text{chr}_{18}^{\text{m}}$ (maternal) and $\text{chr}_{18}^{\text{p}}$ (paternal) 表示 from which parent it is inherited.
  • 我们 conceptually 会把 $\text{chr}_{18}^{\text{m}}$ 和 $\text{chr}_{18}^{\text{p}}$ 给 pair up 起来，并称它俩是 homologous chromosomes (或 homologs for short),
    • homologous 的原义是指 identical to one another in shape and size
      • 但这明显不意味着 “identical in sequence”
    • $\text{chr}_{18}^{\text{m}}$ and $\text{chr}_{18}^{\text{p}}$ are homologs to each other, and only to each other.
    • For females, $\text{X}$ and $\text{X}$ are homologs to each other, and only to each other.
    • For males, $\text{X}$ and $\text{Y}$ are not homologs, they are heterologs
    • 我们说这是 conceptually paired up 是因为在 cell 中，$\text{chr}_{18}^{\text{m}}$ 和 $\text{chr}_{18}^{\text{p}}$ 自由游动的，它们之间没有任何的物理结构连接，即使在细胞分裂期间也没有

[!info] 我们可以把 homology 表示为一个 equivalence relation $\overset{\text{H}}{\sim}$

Definition:

  • For autosomes, $\text{chr}_{i}^{\text{m}} \overset{\text{H}}{\sim} \text{chr}_{j}^{\text{p}} \iff i = j.$
  • For allosomes, $\alpha \overset{\text{H}}{\sim} \beta \iff \alpha = \beta.$

$\blacksquare$

但 $\text{chr}_{18}$ 往往是歧义的，需要看 context，它可以表示：

  1. the general chromosome type, like No. $18$ in all autosomes
  2. one homolog, either $\text{chr}_{18}^{\text{m}}$ or $\text{chr}_{18}^{\text{p}}$
  3. the pair $\text{chr}_{18}^{\text{m}} + \text{chr}_{18}^{\text{p}}$

数量关系上有：

  • Every human cell has $23$ pairs, that’s $46$ chromosomes
  • $1$ chromosome has $2$ strands
  • So every human cell has $92$ strands

3. Coordinates Systems / Upstream & Downstream / TSS Distance

我们前面一路从 DNA zoom in 到 chromosome，现在进一步 zoom in 到 strand：

  • chromStart and chromEnd are columns from table snp142 of database hg19 in UCSC Genome Browser
  • txStart and txEnd are columns from table ensGene of database hg19 in UCSC Genome Browser
  • 0-based coordinate system is used here

3.1 Coordinates Systems

参考 Tutorial: Cheat Sheet For One-Based Vs Zero-Based Coordinate Systems:

  • 0-based：
    • UCSC Genome Browser
    • BED, BAM formats
  • 1-based
    • HGMD
    • Ensembl
    • GFF, SAM, VCF formats
  • 转换规则：
    • $chromStart_{0} = chromStart_{1} - 1$
    • $chromEnd_{0} = chromEnd_{1}$

3.2 Upstream & Downstream

3.3 Directions of Strands

  • 参考 Question: Forward And Reverse Strand Conventions
  • This designation of (+)/(-) strand is arbitrary.
    • Once fixed, the (+) strand determines the direction of coordinate axis;
    • then (-) strand goes reversely.
  • A gene $g$ can be on the (+) strand or (-) strand:
    • The strand that $g$ is on is called $g$’s coding strand (a.k.a. its sense strand).
    • The other strand is called $g$’s template strand (a.k.a. its antisense strand)
    • If $\operatorname{strand}(g) =$ (+) $\Rightarrow \operatorname{TSS}(g) = g.txStart$
    • If $\operatorname{strand}(g) =$ (-) $\Rightarrow \operatorname{TSS}(g) = g.txEnd$
      • N.B. $g.txStart < g.txEnd$ always holds

3.4 TSS Distance

  • TSS: Transcription Start Site`
    • TSS distance: actually means “distance to TSS”
  • Given a SNP $s$ and a gene $g$:
    • If $\operatorname{strand}(g) =$ (+) $\Rightarrow \operatorname{TSS-dist}(s,g) = s.chromStart - g.txStart$;
    • If $\operatorname{strand}(g) =$ (-) $\Rightarrow \operatorname{TSS-dist}(s,g) = g.txEnd - s.chromStart$.
    • In other words, suppose:
      • $\operatorname{strand}(g) = \begin{cases} 1 & \text{ g is on (+) strand} \newline -1 & \text{otherwise} \end{cases}$
      • $\operatorname{TSS}(g) = \begin{cases} g.txStart & \text{ g is on (+) strand} \newline g.txEnd & \text{otherwise} \end{cases}$
        • $\Rightarrow \operatorname{TSS-dist}(s,g) = (s.chromStart - \operatorname{TSS}(g)) \times \operatorname{strand}(g)$
    • If $s$ is in the upstream of $g$, $\operatorname{TSS-dist}(s,g) < 0$, whichever strand $g$ is on
    • If $s$ is in the downstream of $g$, $\operatorname{TSS-dist}(s,g) > 0$, whichever strand $g$ is on

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