Estimating the Human Mutation Rate: Phylogenetic Method

This is the third in a series of posts on human mutation rates and their implication(s). The first two were ...

What Is a Mutation?
Estimating the Human Mutation Rate: Biochemical Method

There are basically three ways to estimate the mutation rate in the human lineage. I refer to them as the Biochemical Method, the Phylogenetic Method, and the Direct Method¹.

The phylogenetic method relies on a known phylogenetic tree to pick out close relatives and the approximate time to the last common ancestor. In the case of humans, we know that chimpanzees and bonobos are our closest cousins and we think that the homind line diverged from the chimp line about 5 million years ago.

On the Effectiveness of Ridicule and Mockery

From time to time we hear from religious people who are upset about the way we treat their faith. They claim that by making fun of their logic and their defense of god we are only making religious people more convinced that they are right. According to them, we'll never convince any religious person to abandon god(s) by using ridicule and mockery.

Perhaps that's right but I very much doubt it. Here's Sam Harris illustrating the power of ridicule to make a point.

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[Hat Tip: lutesuite]

ENCODE & Junk and Why We Call Them IDiots

The Intelligent Design Creationists have been following the debate over the ENCODE results. For them this is a serious issue since they are committed to the idea that well-designed genomes should not be full of junk. You'd think that the IDiots would make an attempt to learn the real scientific issues at stake.

Let's see how andyjones does on Uncommon Descent: Function, the evolution-free gospel of ENCODE. He says,

Apparently, ENCODE are to be criticised for using an ‘evolution-free’ definition of function. Yep, you heard that right. You thought that function was function was function, but oh no, you must use a evolution-y definition or you will not get the ‘correct’ evolution-y answer. It seems awfully like you need to presuppose Darwinism or you will not find Darwinism. Can that be right?

The excuse for this is some interesting Darwinian philosophy (or do I mean sophistry? – make up your mind below): the authors believe that function means nothing (is purely subjective) unless it is selected for. For example, the heart causes the pericardium (the membrane around the heart) to not collapse by filling space, so we could call that a function, but it is selected for pumping blood.

....

Amongst other things the ENCODE authors are lambasted for not distinguishing between ‘Junk DNA’ and ‘Garbage DNA’. No seriously, ‘junk’ now means stuff that is functional, but not used very often, but could be used, like stuff in your attic is ‘junk’. It is different from ‘garbage’, which is the stuff that you would put straight in the bin. ‘junk’ is now a rather misleading word for ‘functional’. So our genome is full of ‘junk’ that is useful and functional, but to a Darwinian it does not count until it starts getting used so that natural selection can get the credit. How convenient! The possibility of design is sidestepped by careful choice of language. Welcome to 1984! A better word might be ‘archived’ rather than ‘junk’.

...

I, and many of us, hold to an ID worldview firstly and most securely because of what we know about prebiotic chemistry and thus the origin of the first life form. Based on that, because I know there has been a designer involved, I think probably a lot of ‘junk’ will turn out to be ‘brought down from the attic’ at various stages of an organisms life, especially in the developing stages. Time will tell.

Scientific means finding out what is actually there. ENCODE are to be praised for doing that. Darwinism has always been about telling creation myths from the point of view of naturalism (roughly, physics only), and shoehorning every fact into the story. ENCODE are now receiving scorn because they did not wait for the Darwinian imprimatur. Intelligent Design people and creationists (in fact everyone who is not a Darwinist) should take courage from this, jump in and start driving forward ordinary mainstream science, but just make sure they sidestep the attempts to sign them up to that cult.

Does anyone still wonder why I refer to Intelligent Design Creationists as IDiots?

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Estimating the Human Mutation Rate: Biochemical Method

This is the second in a series of posts on human mutation rates and their implication(s). The first one was ...
What Is a Mutation?

There are basically three ways to estimate the mutation rate in the human lineage. I refer to them as the Biochemical Method, the Phylogenetic Method, and the Direct Method.

The biochemical method relies on the well-known fact that the vast majority of mutations are due to errors in DNA replication. Since we know a great deal about the replication complex and the biochemistry of the reactions, we can calculate a mutation rate per DNA replication based on this knowledge. The details are explained in a previous post [Mutation Rates]. I'll give a brief summary here.

The overall error rate of DNA polymerase in the replisome is 10^-8 errors per base pair. Repair enzymes fix 99% of these lesions for an overall error rate of 10^-10 per bp. That means one mutation in every 10 billion base pairs that are replicated.

Theme

Mutation

-definition
-mutation types
-mutation rates
-phylogeny
-controversies
The human haploid genome is 3.2 × 10⁹ bp. [How Big Is the Human Genome?] [How Much of Our Genome Is Sequenced? ]. That means that on average there are 0.32 mutations introduced every time the genome is replicated. In the male, there are approximately 400 cell divisions between zygote and the production of a sperm cell.¹ This gives a total of about 128 new mutations in every sperm cell. In the female, there are about 30 cell divisions between zygote and the production of egg cells. That's about 10 new mutations in every egg cell.

Adding these together gives us about 138 new mutations in every zygote. Let's round this down to 130. Thus the estimate from the Biochemical Method is ..

130 mutations per generation

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[Image Credit: Wikipedia: Creative Commons Attribution 2.0 Generic license]

1. This depends on the age of the man when he has children. The value used here is approximately the average for a 30 year old man.

Monday's Molecule #200

This is the 200th Monday's Molecule. I started this series back on November 13, 2006. Today's molecule is a repeat of that first one. Let's see if readers in 2013 can do better than those in 2006! The last "Monday's Molecule" was puromycin [Monday's Molecule #199]. The winners were Bell Gunn and River Jiang. River needs to contact me by email to set up a lunch date. I'm going to try and treat all the previous winners this week so if I owe you a lunch you should get in touch right away to collect.

The mystery molecule is an aldohexose. There are 16 different aldohexoses. The structures and names of 8 of them are show below in order to help you out.

This is a tough one. You have to know several carbohydrate naming conventions and you have to understand Fischer projections. Good luck.



Post your answer as a comment. I'll hold off releasing any comments for 24 hours. The first one with the correct answer wins. I will only post mostly correct answers to avoid embarrassment. The winner will be treated to a free lunch.

There could be two winners. If the first correct answer isn't from an undergraduate student then I'll select a second winner from those undergraduates who post the correct answer. You will need to identify yourself as an undergraduate in order to win. (Put "undergraduate" at the bottom of your comment.)

Michael Behe in Toronto: "Evidence of Design from Biology"

Michael Behe gave a talk on the second day of his visit to Toronto (November 16, 2012). This event was sponsored by religious groups even though Intelligent Design has nothing to do with religion—it's strictly a scientific theory.

The video of his first talk is: "What Are the Limits of Darwinism?". Here's his second talk entitled "Evidence of Design from Biology." There were about 100 people in the audience. I'd guess that half of them were supporters and half were skeptics.

Here's the summary of his talk.

• Design is not mystical. Deduced from physical structure of a system
• Everyone agrees aspects of biology appear designed
• There are structural obstacles to Darwinian evolution
• Grand Darwinian claims rest on undisciplined imagination
• Bottom line: Strong evidence for design, little evidence for Darwinism

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Happy Saint Patrick's Day!

One of the cool things about studying your genealogy is that you can find connections to almost everyone. This means you can celebrate dozens of special days. In my case it was easy to find ancestors from England, Scotland, Netherlands, Germany, France, Spain, Poland, Lithuania, Belgium, Ukraine, Russia, United States, and, of course, Ireland.

We will be celebrating St. Patrick's Day today. It's rather hectic keeping up with all the national holidays but somebody has to keep the traditions alive!

Here's my Irish connection.¹ The shortest connection is to the parents of my grandmother. My great-grandfather was Thomas (Keys) Foster, born in County Tyrone on September 5, 1852. He immigrated to Canada in 1876. Thomas married Eliza Ann Job, born in Fintona, County Tyrone on August 18, 1852. She immigrated to Canada in 1877.

Thomas and Eliza settled in Saskatchewan in 1883 and that's where my grandmother was born. Other ancestors in this line came from the adjacent counties of Donegal (surname Foster) and Fermanagh (surnames Keys, Emerson, Moore) and possibly Londonderry (surname Job).

My paternal grandfather's father was William Findley Docherty (1852-1920). Many of his ancestors were Irish but his DNA was considerably diluted by contamination from Scots.

That makes me at least one quarter Irish² and entitles me to drink beer and wear green. My children, however, are only one eighth Irish. They aren't allowed to drink beer.


Happy St. Patrick's Day (2011)
Happy St. Patrick's Day (2010)
Happy St. Patrick's Day (2009)
Happy St. Patrick's Day (2008)
Happy St. Patrick's Day (2007)
Niall Nóigiallach - Niall of the Nine Hostages

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1. You don't have to be Irish or have Irish ancestors to celebrate St. Patrick's Day.

2. With the proviso that my Irish great-grandparents are probably descended from English setters who came to Ireland in the 1600s. I usually don't mention this on St. Patrick's day.

The Purpose of "The Scientific Dissent from Darwin" List

A few years ago the IDiots tried to collect a list of credible scientists who supported creationism. They created a statement called "The Scientific Dissent from Darwin." It goes like this ...

We are skeptical of claims for the ability of random mutation and natural selection to account for the complexity of life. Careful examination of the evidence for Darwinian theory should be encouraged.

Only an IDiot would claim that supporters of this statement are also creationists. Many atheist scientists, including me, would agree with the statement. Nevertheless, if you look at the list of people who signed [Scientific Dissent from Darwin List] you'll not find very many evolutionary biologists because we all know that the IDiots will misuse this list.

A few days ago someone named Joshua Youngkin posted to Evolution News & Views (sic) in response to a question about the list. According to Youngkin, the list "is a thorn in the side of those who say there's no scientific debate over whether evolution works in a completely naturalistic fashion."

Why is that? The statement doesn't say anything about god or naturalism. This is exactly the kind of doubletalk you expect from IDiots.

Later on in the post Joshua Youngkin says,

The Dissent from Darwin statement counters and preempts any claim that (1) there is no scientific dissent over how evolution happens, by what means, that is, or that (2) it is unscientific to be skeptical of the proposition that natural selection and random mutation together satisfactorily explain the development of life over time.

There are plenty of ways to "preempt" such a false claim. Reading the scientific literature is one.

The list does serve one important purpose and for that we are truly thankful. It's the best list of Ph.D IDiots that I know of. It's easy to find your local IDiots using a simple word search. For example, I found these names from the University of Toronto: Stephen J. Cheesman Ph.D. Geophysics and Alfred G. Ratz Ph.D. Engineering Physics. Unfortunately, as I pointed out some years ago [I'm not a Darwinist, but I Ain't Signing], neither of these gentlemen are listed in the university phone book and they are not on the University website so we don't know what they are up to these days.

Project Steve with 1249 signatures, is an excellent parody of the creationist list.

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On the Meaning of the Word "Function"

A lot of the debate over ENCODE's publicity campaign concerns the meaning of the word "function." In the summary article published in Nature last September the authors said, "These data enabled us to assign biochemical functions for 80% of the genome ...." (The ENCODE Project Consortium, 2012).

Here's how they describe function.

Operationally, we define a functional element as a discrete genome segment that encodes a defined product (for example, protein or non-coding RNA) or displays a reproducible biochemical signature (for example, protein binding, or a specific chromatin structure).

What, exactly, do the ENCODE scientists mean? Do they think that junk DNA might contain "functional elements"? If so, that doesn't make a lot of sense, does it?

Ewan Birney tried to address this definitional morass on his blog [ENCODE: My own thoughts] where he says ....

It’s clear that 80% of the genome has a specific biochemical activity – whatever that might be. This question hinges on the word “functional” so let’s try to tackle this first. Like many English language words, “functional” is a very useful but context-dependent word. Does a “functional element” in the genome mean something that changes a biochemical property of the cell (i.e., if the sequence was not here, the biochemistry would be different) or is it something that changes a phenotypically observable trait that affects the whole organism? At their limits (considering all the biochemical activities being a phenotype), these two definitions merge. Having spent a long time thinking about and discussing this, not a single definition of “functional” works for all conversations. We have to be precise about the context. Pragmatically, in ENCODE we define our criteria as “specific biochemical activity” – for example, an assay that identifies a series of bases. This is not the entire genome (so, for example, things like “having a phosphodiester bond” would not qualify). We then subset this into different classes of assay; in decreasing order of coverage these are: RNA, “broad” histone modifications, “narrow” histone modifications, DNaseI hypersensitive sites, Transcription Factor ChIP-seq peaks, DNaseI Footprints, Transcription Factor bound motifs, and finally Exons.

That's about as clear as mud.

We all know what the problem is. It's whether all binding sites have a biological function or whether many of them are just noise arising as a property of DNA binding proteins. It's whether all transcripts have a biological function or whether many of those detected by ENCODE are just spurious transcripts or junk RNA. These questions were debated extensively when the ENCODE pilot project was published in 2007. Every ENCODE scientist should know about this problem so you might expect that they would take steps to distinguish between real biological function and nonfunctional noise.

Their definition of "function" is not helpful. In fact, it seems deliberately designed to obfuscate.

Let's see how other scientist interpret the ENCODE results. In a News & Views article published in Nature last September, Joseph R, Ecker (Salk Institute scientist) said ...

One of the more remarkable findings described in the consortium's 'entré' paper is that 80% of the genome contains elements linked to biochemical function, dispatching the widely held view that the human genome is mostly 'junk DNA.'

That makes at least one genomics worker who thinks that "biochemical function" and junk DNA are mutually exclusive.

Recently a representative of GENCODE responded to Dan Graur's criticism [On the annotation of functionality in GENCODE (or: our continuing efforts to understand how a television set works)]. This person (JM) says ...

Q1: Does GENCODE believe that 80% of the genome is functional?

As noted, we will only discuss here the portion of the genome that is transcribed. According to the main ENCODE paper, while 80% of the genome appears to have some biological activity, only “62% of genomic bases are reproducibly represented in sequenced long (>200 nucleotides) RNA molecules or GENCODE exons”. In fact, only 5.5% of this transcription overlaps with GENCODE exons. So we have two things here: existing GENCODE models largely based on mRNA / EST evidence, and novel transcripts inferred from RNAseq data. The suggestion, then, is that there is extensive transcription occurring outside of currently annotated GENCODE exons.

There's another scientist who thinks that 80% of the genome has some biological activity in spite of the fact that the ENCODE paper says it has "biochemical function." I don't think "biological activity" is compatible with "junk DNA," but who knows what they think?

Since this person is part of the ENCODE team, we can assume that at least some of the scientists on the team are confused.

The Sanger Institute (Cambridge, UK) was an important player in the ENCODE Consortium. It put out a press release on the day the papers were published [Google Earth of Biomedical Research]. The opening paragraph is ...

The ENCODE Project, today, announces that most of what was previously considered as 'junk DNA' in the human genome is actually functional. The ENCODE Project has found that 80 per cent of the human genome sequence is linked to biological function.

It looks like the Sanger Institute equates "biochemical function" and "biological function" and it looks like neither one is compatible with junk DNA.

I think the ENCODE leaders, including Ewan Birney, knew exactly what they were doing when they defined function. They meant "biological function" even though they equivocated by saying "biochemical function." And they meant for this to be interpreted as "not junk" even though they are attempting to backtrack in the face of criticism.

Function Wars
(My personal view of the meaning of function is described at the end of Part V.)

• 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"?

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The ENCODE Project Consortium (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489: 57-74. (E. Birney, corresponding author)

Anonymous Nature Editors Respond to ENCODE Criticism

There are now been four papers in the scientific literature criticizing the way ENCODE leaders hyped their data by claiming that most of our genome is functional [see Ford Doolittle's Critique of ENCODE ]. There have been dozens of blog postings on the same topic.

The worst of the papers were published by Nature—this includes the abominable summary that should never have made it past peer review (Encode Consortium, 2012).

The lead editor on the ENCODE story was Brendan Maher and he promoted the idea that the ENCODE results showed that most of our genome has a function [ENCODE: The human encyclopaedia]

The consortium has assigned some sort of function to roughly 80% of the genome, including more than 70,000 ‘promoter’ regions — the sites, just upstream of genes, where proteins bind to control gene expression — and nearly 400,000 ‘enhancer’ regions that regulate expression of distant genes.

Misconceptions about Random Genetic Drift

Genetic Drift

Evolutionary change that occurs by random sampling of different alleles from one generation to the next. This causes nonadaptive evolutionary change.

Jerry Coyne
"Why Evolution Is True"There seem to be two important themes in the current pedagogical literature on science education. One of them is about student-centered learning—a concept I think we should all adopt. The other is about student misconceptions and how to deal with them. Much of the literature suggests that misconceptions need to be confronted and corrected. They can't be corrected by simply presenting the "correct" information. You need to actually address the misconception and show why it is wrong. This is a form of "teach the controversy" and that's not going to sit well with many American supporters of evolution.

Here's an interesting paper on "Biology Undergraduates’ Misconceptions about Genetic Drift" (Andrews et al., 2012). The abstract covers all the important points.

Barry Arrington Demonstrates IDiot Logic

A few years ago Barry Arrington came up with this killer argument against evolution [see Question: How Can We Know One Belief Selected for By Evolution is Superior to Another?].

Theist: You say there is no God.
Evolutionary Materialist [EM]: Yes.
Theist: Yet belief in God among many (if not most) humans persists.
EM: I cannot deny that.
Theist: How do you explain that?
EM: Religious belief is an evolutionary adaption.
Theist: But you say religious belief is false.
EM: That’s correct.
Theist: Let me get this straight. According to you, religious belief has at least two characterizes: (1) it is false; and (2) evolution selected for it.
EM [looking a little pale now, because he’s just figured out where this is going]: Correct.
Theist: You believe the Neo-Darwinian Synthesis [NDS] is true.
EM: Of course.
Theist: How do you know your belief in NDS is not another false belief that evolution has selected for?
EM: ___________________

Our materialist friends are invited to fill in the blank.

Ford Doolittle's Critique of ENCODE

Ford Doolittle has never been one to shy away from controversy so it's not surprising that he weighs in against the misleading publicity campaign launched by ENCODE leaders last September (Doolittle, 2013). Recall that Ewan Birney and other prominent members of the consortium promoted the idea that our genome contained an extensive array of regulatory elements and that 80% of our genome was functional [Ewan Birney: Genomics' Big Talker] [ENCODE Leader Says that 80% of Our Genome Is Functional] [The ENCODE Data Dump and the Responsibility of Scientists].

This is the fourth paper that's critical of the ENCODE hype. The first was Sean Eddy's paper in Current Biology (Eddy, 2012). The second was a paper by Niu and Jiang (2012), and the third was a paper by Graur et al. (2013). In my experience this is unusual since the critiques are all directed at how the ENCODE Consortium interpreted their data and how they misled the scientific community (and the general public) by exaggerating their results. Those kind of criticisms are common in journal clubs and, certainly, in the blogosphere, but scientific journals generally don't publish them. It's okay to refute the data (as in the arsenic affair) but ideas usually get a free pass no matter how stupid they are.

In this case, the ENCODE Consortium did such a bad job of describing their data that journals had to pay attention. (It helps that much of the criticism is directed at Nature and Science because the other journals want to take down the leaders!)

What's Wrong with This Statement?

Read the following statement from the Wikipedia article on the Genetic Code.

... the genetic code used by all known forms of life is nearly universal with few minor variations. This suggests that a single evolutionary history underlies the origin of the genetic code.

What wrong with this statement? Cornelius Hunter says that the statement "... is false—at least from a scientific perspective" [Here is Why the DNA Code is a Problem]. Can you guess why this IDiot would make such a claim?

In contrast, an anonymous source at Uncommon Descent asks, "Does the Genetic Code Bear A Signature of Intelligence?." He/she posts the following abstract ...

It has been repeatedly proposed to expand the scope for SETI, and one of the suggested alternatives to radio is the biological media. Genomic DNA is already used on Earth to store non-biological information. Though smaller in capacity, but stronger in noise immunity is the genetic code. The code is a flexible mapping between codons and amino acids, and this flexibility allows modifying the code artificially. But once fixed, the code might stay unchanged over cosmological timescales; in fact, it is the most durable construct known. Therefore it represents an exceptionally reliable storage for an intelligent signature, if that conforms to biological and thermodynamic requirements. As the actual scenario for the origin of terrestrial life is far from being settled, the proposal that it might have been seeded intentionally cannot be ruled out. A statistically strong intelligent-like “signal” in the genetic code is then a testable consequence of such scenario. Here we show that the terrestrial code displays a thorough precision-type orderliness matching the criteria to be considered an informational signal. Simple arrangements of the code reveal an ensemble of arithmetical and ideographical patterns of the same symbolic language. Accurate and systematic, these underlying patterns appear as a product of precision logic and nontrivial computing rather than of stochastic processes (the null hypothesis that they are due to chance coupled with presumable evolutionary pathways is rejected with P-value < 10–13). The patterns display readily recognizable hallmarks of artificiality, among which are the symbol of zero, the privileged decimal syntax and semantical symmetries. Besides, extraction of the signal involves logically straightforward but abstract operations, making the patterns essentially irreducible to natural origin. Plausible ways of embedding the signal into the code and possible interpretation of its content are discussed. Overall, while the code is nearly optimized biologically, its limited capacity is used extremely efficiently to pass non-biological information.

According to Uncommon Descent, the article is written by two scientists. They turn out to be two mathematicians from the Republic of Kazakhstan [The “Wow! signal” of the terrestrial genetic code].

Can you guess why the IDiots would believe such a ridiculous claim?

I wonder if Cornelius Hunter thinks this is science?

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Monday's Molecule #199

The last "Monday's Molecule" was phycoerythrin [Monday's Molecule #198]. The winner was Piotr Gasiorowski.

This week's molecule can do some very bad things to certain cells. You just have to give the common name and briefly explain what it does and how it works.

Post your answer as a comment. I'll hold off releasing any comments for 24 hours. The first one with the correct answer wins. I will only post mostly correct answers to avoid embarrassment. The winner will be treated to a free lunch.

There could be two winners. If the first correct answer isn't from an undergraduate student then I'll select a second winner from those undergraduates who post the correct answer. You will need to identify yourself as an undergraduate in order to win. (Put "undergraduate" at the bottom of your comment.)