Estimating the Human Mutation Rate: Direct Method

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

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

The Biochemical Method is based on our knowledge of biochemistry and DNA replication as well as estimates of the number of cell divisions between zygote and egg. It gives a value of 130 mutations per generation. The Phylogenetic Method depends on the fact that most mutations are neutral and that the rate of fixation of alleles is equal to the mutation rate. It also relies on a correct phylogeny. The Phylogenetic Method gives values between 112-160 mutations per generation. These two methods are pretty much in agreement.

The Direct Method involves sequencing the entire genomes of related individuals (e.g. mother, father, child) and simply counting the new mutations in the offspring. You might think that the Direct Method gives a definitive result that doesn't rely on any assumptions, therefore it should yield the most accurate result. The other two methods should be irrelevant.

This would be true if the Direct Method were as easy as it sounds but things are more complicated.

Michele Bachmann Lies About Socialized Medicine

Michele Bachmann is an IDiot but I try to avoid commenting on the fact that she's a duly-elected congresswoman from Minnesota. If Americans want to elect someone like her to run their country then that's up to them.

People in the civilized world outside of the USA are puzzled by some of the things she says—they wonder how she can get away with such statements and still be elected. Her recent speech on "Obamacare" in Congress is a case in point. You can see it in the video below. This is the speech where she says, ""Repeal this failure [Obamacare] before it literally kills women, kills children, kills senior citizens."


Later on her spokesman, Dan Kotman, issued the following statement.

Obamacare is forcing doctors into the employ of cost-cutting hospitals, gives government the authority to determine services that will and will not be covered, has a board independent of Congress that can cut payments for care, and allows the Secretary of Health and Human Services to force all health plans to eliminate any doctor that doesn't practice medicine the government's way. The history of government-run health care systems around the world is a history of denial, delay and sadly even death.

It's one thing to attack "Obamacare" but when she attacks healthcare in Canada and all other civilized countries, that's a different issue.

Let me remind you that there's tons of data showing that people live longer in other countries and they survive cancer better. Infant mortality is lower in other countries. And this success is achieved at lower cost than health care in the USA. In other words, Michele Bachmann is dead wrong when she says that socialized medicine is a "history of death."

As I was preparing this post I stumbled across a video of Senator Jeff Sessions of Alabama defending American health care in the Senate of the United States Congress. Are Americans embarrassed by speeches like this or is this typical of Americans who have been elected to the Senate? Is it the best that Alabama has to offer?

Sen. Jeff Sessions: 'So We've Got People Who Die Sooner'

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Mocking Friedman's MOOCs

Thomas L. Friedman is the Op-ed columnist for foreign affairs at the New York Times. He has won three Pulitzer Prizes (1983, 1988, 2002).

According to Wikipedia, Friedman has an undergraduate degree from Brandeis University (Boston, USA) and a Master's degree from Oxford (UK). He taught a class at Brandeis in 2006 but as far as I can tell that's his only experience with university outside of being a student. He does not appear to be an educator and he doesn't appear to have any expertise in pedagogy.

That hasn't prevented him from writing three opinion pieces on the imminent demise of universities and the glorious future of online courses—especially MOOCs (Massive Open Online Courses).

Come the Revolution May 15, 20012
Revolution Hits the Universities January 26, 2003
The Professors’ Big Stage: March 5, 2013

Goodbye John Witton

I'm rather proud of the fact that few people have been banned from this blog. That's why it's worth a special post when someone gets banned.

John Witton can no longer post comments on Sandwalk. He has proven that he is a liar when he backed out of his offer to pay $1000 to anyone who would answer his questions [John Witton Will Pay You $1000 to Answer One of His Questions].

More importantly, he continues to spam the comments sections of several posts. Nothing that he says is relevant to the topic and many of his recent comments are delusional.

Goodbye John Witton.

He joins a special group of people who have been banned from Sandwalk: Joe (Joseph) Bozorgmehr (Atheistoclast), David Roemer, and Douglas Dobney. The fastest and easiest way to get banned is to try and intimidate me (or any other blogger) by writing nasty letters to our employers and/or bosses. That's how David Roemer, and Douglas Dobney got banned. Equally efficient is to post lots of comments attacking my integrity and accusing me of all sorts of vile (untrue) things (Atheistoclast). Witton took the slow route to being banned.

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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.