Chaper 5: The Big Picture

Introduction

DNA sequencing and assembly. Cost of sequencing. (pp. 116-118)

A typical gene

DNA sequences are depositied in GenBank. The gene for triose phosphate isomerase (TPI1) is a typical gene. Decoding a protein-coding gene. (pp. 118-122)

Annotators interpret the genome

Human annotators must interpret the DNA sequence. (pp. 122-123)
[ Contaminated genome sequences]

How much of the genome has been sequenced?

About 95% of the genome has been sequenced in the standard reference genome. The rest is estimated from the size of the gaps giving a total of 3.1 Gb. The complete telomere-telomere sequence of T2T-CHM13 is also 3.1 Gb. (pp. 123-125)
[Karen Miga and the telomere-to-telomere consortium] [A complete human genome sequence (2022)] [What do we do with two different human genome reference sequences?] [How big is the human genome (2023)?]

Whose genome was sequenced?

The Celera sequence was mostly Craig Venter's genome. The IHGP standard reference genome was originally a composite of several difference individuals from Buffalo (New York, USA). (pp. 125-126)

How many genes?

The original genome sequence predicted 30,000-40,000 protein-coding genes but that number has dropped to about 20,000 in the current standard reference genome. There are about 5,000 noncoding genes but this number is disputed. Introns take up most of a protein-coding gene and introns are mostly junk DNA. (pp. 126-128)
[Are introns mostly junk?]

Pseudogenes

There are abot 15,000 pseudogenes derived from protein-coding genes. The number derived from noncoding genes is not known. Pseudogenes account for about 5% of the genome. (p. 128)

Regulatory sequences

If we assume about 200 bp of regulatory sequence for each gene then regulatory sequences account for less than 0.2% of your genome. Many scientists believe this number should be much higher. (pp. 128-129)

Origins of replication

There are about 30,000-50, 000 functioning origins of replication accounting for <0.3% of your genome. (pp. 129-130)

Centromeres

About 1% of your genome is occupied by centromeres. (p. 130)
[Centromere DNA] [Minimum Centromere Size in Plants]

Telomeres

Telomere sequences are about 0.1%. (pp. 130-131)
[Telomeres]

Scaffold Attachment regions (SARs)

SARs are required for chromatin organizaton and it's not clear how much DNA sequence is required. Assuming 100,000 loops and 100 bp of SAR per loop gives 0.3% of the genome. (p. 131)

Transposons

About 55% of the genome contains transposon-related and virus-related sequences. They are scattered throughout the genome including within introns. (pp. 131-132)

Viruses

Defective viruses take up about 9% of the genome and functional, dormant, viruses account for less than 0.1%. (p. 132)

Mitochondrial DNA

Less than 0.01% of your genome is occupied by mitochondrial DNA fragments. (p. 132)

How much of our genome is functional?

Adding up all the known functional sequences gives a value of about 4% functional. The actual amount is probably closer to 8-10% based on sequence conservation. The total amount of presumed junk DNA comes to 89%. About 90% of your genome is junk. (pp. 132-133)
[The 20th anniversary of the human genome sequence: 4. Functional DNA in our genome]

What is junk DNA?

Junk DNA is DNA that can be deleted without reducing the fitness of the individual. The debate is not whether junk DNA exists (it does) but over the amount of junk DNA. Opponents of junk DNA think that it would have been eliminated by natural selection if it were really junk. This is a common view in the popular press and even in the scientific literature. My vew is that genomes are sloppy and natural selection isn't capable of purging junk DNA in species with large genomes. (pp. 133-135)
[Identifying functional DNA (and junk) by purifying selection]

Notes for Chapter 5 (p. 324)

Chapter 4: Why Don't Mutations Kill Us?

Introduction

Gregor Mendel and mutations. Spontaneous mutations. Rate of mutation. (pp. 82-83)
[Mutation, Randomness, & Evolution]

Why aren’t we extinct? - a 100-year old problem

History of mutation load (genetic load). Prediction of 30,000 genes. (pp. 83-84)
[What Is a Mutation?] [Genetic Load, Neutral Theory, and Junk DNA]

Biochemical mutation rate

Knowing the overall error rate of DNA replication (10^-10 mutations per base pair) and the number of cell divisions in the germ line gives an average of 138 new mutations per generation. (pp. 84-85)
[Parental age and the human mutation rate ] [Estimating the Human Mutation Rate: Biochemical Method] [Human Y Chromosome Mutation Rates] [Mutation Rates]

Phylogenetic mutation rate

If you know the number of generations since the time of a common ancestor then you can calculate a mutation rate by looking at sequences that are evolving at the neutral rate. (pp. 85-86)
[Estimating the Human Mutation Rate: Phylogenetic Method] [Calculating time of divergence using genome sequences and mutation rates (humans vs other apes)]

   Box: Tick, tock, the molecular clock (p. 87)
   [The Modern Molecular Clock] [Can some genomes evolve more slowly than others?]
   [Reading the Entrails of Chickens] [Calibrating the Molecular Clock]

The direct method of calculating mutation rate

Comparing the sequences of a child and both parents gives you the number of new mutations per generation. (p. 88)
[Direct Measurement of Human Mutation Rate] [Parental age and the human mutation rate] [Estimating the Human Mutation Rate: Direct Method] [Human Mutation Rates] [Human mutation rates - what's the right number?] [Somatic cell mutation rate in humans]

You are not Craig Venter

Craig Venter's genome sequence was the first one to include all 46 chromosomes separately. The amount of heterogeneity in human genomes means that no two individuals are alike. (pp. 89-90)
[What happens when twins get their DNA tested?] [Genetic variation in the human population] [Genetic variation and the complete human genome sequence] [Sequencing both copies of your diploid genome] [Sequencing human diploid genomes] [All about Craig]

Revisiting the genetic load argument

Given the mutation rate and the probability of deleterious mutations, only a small percenage of the human genome can be susceptible to mutation or our species would go extinct. (pp. 90-94)
[Revisiting the genetic load argument with Dan Graur]

   Box: Human gene knockouts (pp. 92-93)

How much of our genome is conserved?

About 8-10% of the DNA sequences in the human genome are conserved in other species. (pp. 94-95)

Defining function

The best definition of function is the maintenance definition that relies on purifying selection. Functional DNA is any stretch of DNA whose deletion from the genome would reduce the fitness of the individual. (pp. 96-98)
[Identifying functional DNA (and junk) by purifying selection] [On the Meaning of the Word "Function"] [The Function Wars: Part I] [The Function Wars: Part II] [The Function Wars: Part III] [The Function Wars: Part IV] [Restarting the function wars (The Function Wars Part V)] [The Function Wars Part VI: The problem with selected effect function] [The Function Wars Part VII: Function monism vs function pluralism] [The Function Wars Part VIII: Selected effect function and de novo genes] [The Function Wars Part IX: Stefan Linquist on Causal Role vs Selected Effect] [The Function Wars Part X: "Spam DNA"?]

   Box: Levels of selection (pp. 99-101)
   [The Function Wars Part XIII: Ford Doolittle writes about transposons and levels of selection]

Why is the evidence of sequence conservation so hard to accept?

There are several arguments against sequence conservation as an indicator of function. (pp. 101-103)

   Box: Deleting DNA to prove that it is junk (pp. 104-105)

Bulk DNA hypotheses

Skeletal DNA hypotheses. The bodyguard hypothesis. Genetic diversity. (pp. 105-110)
[Teaching about genomes using Nessa Carey's book: Junk DNA]

Medical relevance

Medical relevance is a weak argument for function because mutations in junk DNA can cause genetic diseases. (pp. 110-112)
[Junk DNA vs noncoding]

Ignoring history

Opponents of junk DNA have propagated a false narrative about the history of junk DNA by claiming that scientists in the late 1960s and early 1970s thought that all noncoding DNA was junk. (pp. 112-115)
[The "standard" view of junk DNA is completely wrong] [Junk DNA vs noncoding DNA] [The surprising (?) conservation of noncoding DNA] [More misconceptions about junk DNA - what are we doing wrong?] [Alan McHughen defends his views on junk DNA] [A University of Chicago history graduate student's perspective on junk DNA] [Nature journalist is confused about noncoding RNAs and junk] [What is the dominant view of junk DNA?]

Notes for Chapter 4 (pp. 321-324)