Evolving dogma: proteins come next - HUIT Sites Hostingsites.fas.harvard.edu/~lsci1a/11-28notes.pdf · Evolving dogma: proteins come next RNA Protein Energy harvesting Locomotion

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Evolving dogma: proteins come next

RNA Protein

Energy harvesting

Locomotion

Sensation

Cell division

Building blocksynthesis

The last stage was the appearance of DNA, the most chemically andstructurally boring of all life’s macromolecules. Once the invention of proteinsynthesis had released RNA from its role as the source of the cell’s catalyticactivities, selection could turn to looking for a chemically more stablemolecule to use for storing information. As David pointed out, eliminating the2’ hydroxyl on ribose converts chemically unstable RNA into DNA, producinga much more chemically stable information carrier. In addition, making theDNA double helical served two purposes, providing a completely generalmechanism for the replication of the genetic material and partially hiding thevulnerable bases from the action of a variety of chemicals.

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Evolving dogma: DNA comes last

Energy harvesting

Locomotion

Sensation

Cell division

Building blocksynthesis

RNA ProteinDNA

“Reverse transcriptase”(first DNA polymerase)

The last stage was the appearance of DNA, the most chemically andstructurally boring of all life’s macromolecules. Once the invention of proteinsynthesis had released RNA from its role as the source of the cell’s catalyticactivities, selection could turn to looking for a chemically more stablemolecule to use for storing information. As David pointed out, eliminating the2’ hydroxyl on ribose converts chemically unstable RNA into DNA, producinga much more chemically stable information carrier. In addition, making theDNA double helical served two purposes, providing a completely generalmechanism for the replication of the genetic material and partially hiding thevulnerable bases from the action of a variety of chemicals.

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Structure and function: Two views of DNA

Structure (Chemist):

sugar 2’ OH gives RNA extra catalytic and binding capacity

Function (Biologist):

RNA was selected for diverse catalytic functions

DNA was selected for structural and chemical stability

Evidence:

Catalytically active DNAs can be created by artificial selection

They are harder to find than catalytically active RNAs

This last step prompts me to revisit the question of why different nucleic acidsmolecules have different shapes as a way of indicating how differentlychemists and biologists think about the same questions. When David told youabout the structures of RNA and DNA he pointed out that DNA has a singleboring shape, whereas RNA molecules come in a glorious range of shapes andsizes. He argued that the primary source of this difference was the extrahydroxyl group of the ribose ring in RNA which gave more conformationalflexibility and more hydrogen bonding opportunities in RNA than DNA.

My perspective is evolutionary. I argue that the difference in the shapes ofDNA and RNA molecules reflects what they were selected to do, rather thantheir intrinsic, chemical potential for forming different structures. RNA datesback to the RNA world where it had to act both as catalyst and informationcarrier, and many of the most structurally interesting RNA molecules,including ribosomal and transfer RNA, retain something of this dual role.Thus in the beginning RNA was selected to be chemically active, and theselection for different chemical activities led to different structures. Incontrast, DNA was selected to be safe, stable, and boring. It’s double helicalstructure is not a reflection of its chemical limits but its limited biological role,where the strands are kept paired to ensure the safe storage and maintenance ofinformation, and only separated briefly to allow for the synthesis of newstrands of RNA during transcription, and new strands of DNA duringreplication.

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Structure and function: Two views of DNA

Structure (Chemist):

sugar 2’ OH gives RNA extra catalytic and binding capacity

Function (Biologist):

RNA was selected for diverse catalytic functions

DNA was selected for structural and chemical stability

Evidence:

Catalytically active DNAs can be created by artificial selection

They are harder to find than catalytically active RNAs

So who’s right? The diplomatic answer is that both arguments have to bepartly true. There is chemical evidence that it’s harder, but not impossible, forDNA rather than RNA to form discrete structures that bind specific molecules.But because it’s not impossible to make DNA molecules that form interestingstructures and perform chemical reactions, it’s hard not to believe that thedifference in the structure of DNA and RNA reflects selection for their verydifferent function at least as much as it does their inherent potential to formdifferent structures.

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Deducing evolution from sequence information:Linus Pauling saw molecules as evolutionary messages

The description of the evolution of the central dogma differs in a fundamentalway from our description what has happened in evolution since the centraldogma appeared in its current form. The actual origin of life is shrouded inmystery, and although many biologists find the idea that life originated withself-replicating RNA molecules compelling, there are others who preferalternative hypotheses. But both camps are agreed on what happenedafterwards because we have very strong evidence for what has happened sinceand the purpose of this section is to present that evidence in its briefest andmost skeletal form. I believe that this is important since repeated surveys overthe last fifty years have failed to find a time when more than half of Americansbelieved in evolution.The evidence for evolution is that we can trace an unbroken line of descent thatconnects every creature living today back to a single common ancestor thatexisted roughly 3 billion years ago. Even when inferences about evolution,like Darwin’s, were based on the appearance and function of current dayorganisms and the appearance and deduced functions of fossils from the past,this was a powerful argument. It became enormously stronger in 1965 whenEmile Zuckerkandl and Linus Pauling (of chemical bond, vitamin C, and anti-nuclear war fame) suggested that the sequences of the same protein derivedfrom different organisms held clues about the evolutionary history andrelationships of the organisms. To paraphrase them, they asked the question“What is the richest source of information about the past history of livingorganisms and how can this information be extracted?” and answered it “Thesequences of proteins and nucleic acids”.

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Question: What is the richest source ofinformation about the past history of livingorganisms and how can this information beextracted

Pauling’s evolutionary Q & A

Answer: The sequences of proteins andnucleic acids

The basic idea is simple. If we assume that mutations arise and areincorporated into a the DNA sequence of any given gene at a roughly constantrate over evolutionary time, we can compare the DNA sequence of that geneand the protein sequence the gene encodes amongst many living organisms anddeduce which organisms are most closely related to each other. We can evenuse statistical methods to make useful inferences about the sequence of theancestral form of the protein in ancestors that are no longer living. It is exactlythis logic that Rob referred to in his discussion of the evolutionary tree of life,and such comparisons offer a straightforward way of assessing evolutionaryrelationships between living organisms..

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Reconstructing Evolution: a monastic analogy

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ATTCTGGAGC

ATTCTGGAGT

ATGCTGGACC

ATGCTTGACC

ATTCTGGAGC

ATGCT?GACC

AT?CT?GA?C

DNA sequences imply an evolutionary tree

time

The idea is shown in cartoon form on this slide, for a small section of a genethat has been sequenced from four different organisms. We start by collectingthe two pairs of sequences that are most similar to each other and arguing thatthe two organisms within a pair must have shared a common ancestor morerecently than either has with a creature that is part of the other pair. Theargument is simply that if mutations rain down and are accepted at a roughlyconstant rate, two DNA (or protein) sequences that are more similar shared acommon ancestor more recently than two DNA sequences that have moredifferences between them. This process of grouping sets of sequences bysimilarity can be continued to create higher and higher levels of organizationleading to the demonstration that the ribosomal RNA of every organism be itE. coli or an elephant is far more similar to that of other organisms than wewould have any right to expect if the organisms had been createdindependently, rather than evolving from a single common ancestor.What I have just said is that evolutionary arguments can make detailedinferences about the past, using a single simple principle. To me, this is anextremely strong argument that the theory that Darwin and Wallace invented isthe correct explanation of the origin and subsequent diversification of life.There is a second argument for evolution that is at least as compelling as thefirst. We can see evolution in action on time scales where important changeshappen within a human lifetime. Examples include the evolution of antibioticresistance in bacteria and DDT resistance in mosquitoes both of which haveoccurred in a single human lifetime, but to me, the most compelling examplesare those that occur within the course of a disease in a single individual.

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AIDS and cancer: evolution in action

AIDS: virus mutates to drug resistanceand to alter cell preference

Cancer: patient’s own cells mutate toescape social rules of cell behavior

The two most medically important examples are AIDS and cancer. As HIVreplicates mutations appear at random at every different position in thegenome. Most of these mutations interfere with viral replication or infectionand are selected against. But, as we have seen, some of them allow the mutantviruses to escape from antibodies the immune system has made to the originalinfecting virus, invade new types of cells, or replicate in the presence of anti-viral drugs. These mutations that help the virus aren’t called into existence bythe various selections and they represent a very tiny fraction of all the differenttypes of mutation that are occurring in the virus, but they are the ones that takeover the population, because the viruses that contain them outcompete theirpredecessors who do not.

AIDS and cancer also give the lie to the notion that evolution is an process for“improving” life. Mutations that benefit HIV by making it resistant to proteaseinhibitors are clearly deleterious for the patient in which they occur. As wewill see, cancer reveals the blindness of evolution even more clearly.Mutations in cancer cells allow them to grow and divide at their host’sexpense, but this is the ultimate in disastrous victory, since the uncheckedgrowth and division of the cancer cells ultimately kills the patient and thecancer cells die with their victim.

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Because viruses are inert outside cells they provide a dramatic demonstrationof what is needed for life. They can replicate because cells provide them withthe building blocks to make the macromolecules that will make new viruses,the energy and enzymes needed to couple those building blocks together, and asheltered and tightly controlled environment for assembling themacromolecules into new viruses. For HIV, only two of the enzymes in theviral life cycle, reverse transcriptase and the viral protease, are encoded by thevirus and provide targets for modern medicine to attack.

The reason that viruses can so easily exploit cells, is that all the same thingsare needed to convert one cell into two. In this sense, viruses are the ultimategatecrashers, uninvited guests who can have a good time at the host’s expenseprecisely because the host needs to provide food, drink, and entertainment forall the guests who were actually invited.

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If viruses are enemies without who descend to exploit cells, must we also dealwith enemies within. Sadly, the answer is yes. Just as an invited guest whodrinks too much can ruin your sophisticated and urbane party as easily as agatecrasher, we are as vulnerable to misbehavior of rogue cells within our ownbodies as we are to viral and microbial enemies from without. As you haveprobably guessed, the rogue cells are cancer cells, and like viruses they exploitthe normal machinery used to produce the cell growth and division thatconverts a fertilized egg into us.

Like AIDS cancer, offers us a way of appreciating the normal behaviors ofcells, understanding how, under special circumstances, the basic principle ofevolution can work against us, and seeing how planning and serendipity cancome together in medicine.

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3A. Cancer: the enemy within

1. An introduction to cancer Alberts, 726-730

2. The germ line and soma Alberts, 293-294a. Multicellularity and the division of laborb. Germ line mutations affect the next generationc. Somatic mutations affect this generation

3. Cell Proliferation and Cancera. Balancing cell birth and deathb. Multiple changes in cell behavior cause cancer

4. The epidemiology of cancer Alberts, 727-735a. Cancer results from multiple mutationsb. Environmental contributions to cancerc. Genetic contributions to cancer

The material you covered in the first half of the course dealt with two largeareas, introducing you to enough chemistry so that you could understand thechemical basis of life, and showing you the remarkable sophistication of thechemistry living cells do, from the passage and expression of geneticinformation by replication, transcription, and translation to the extraordinaryspeed and subtlety of the reactions carried out by enzymes, nature’s catalysts.The second half of the course will make use of these concepts and refer back tothem, but it will also introduce the second amazing capacity of living cells andorganisms, their ability to monitor their environments and interiors and use thisinformation to precisely regulate the vast number of chemical reactions theycontain in a way that helps them fulfill their evolutionary destiny of leaving asmany viable offspring as possible. This regulation has to be flexible enough toallow a given species to survive and prosper in a wide range of environmentsand for multicellular creatures like us, it has to make sure that the behavior of avast number of individual cells and the chemical reactions inside them areregulated in the interest of the enormous cellular cooperative that constitutes ahuman being.

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Just as we did in the first half of the course, we use a disease to illustrate theseconcepts. Cancer is our second major story because it shows what happenswhen biological regulation fails and members of the cellular cooperative nolonger obey its rules. This section will introduce the basic biology of cancer bydescribing the fundamental features of the disease and the factors that determinewho suffers from it. The following two lectures will describe how normal cellsgrow and divide, and will deal with the challenges they must solve so that theycan produce daughters that are free of mutations and do so only where and whenthe production of new cells will help rather than harm us. Finally, the last threelectures of the course discuss how cells choose which genes to express, and thechemical details of a class of enzymes called protein kinases, which regulatethe activity of an enormous range of biological reactions. We will close bydiscussing a particular form of cancer called chronic myelogenous leukemia orCML and a remarkable drug called Gleevec which comes close to curingpatients who suffer from it. Both in our general introduction, and in ourtreatment of CML, we will see that like AIDS, cancer is an evolutionary disease,in which the pathogenic agent, in this case our own cells, changes during thecourse of the disease thus, outwitting our bodies and the medical profession’sdefenses.

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This section of the course begins our discussion of cancer as the enemy within.It starts with an introduction to cancer and then moves on to consider theseparation between two cell lineages in our bodies, the germ line and the soma,and the different implications of mutations in these two types of cells. Next, wediscuss the need to carefully regulate cell birth and cell death duringdevelopment and adult life to ensure that our bodies function as well behavedcell cooperatives where there are neither too few or too many of the 100 or sodifferent types of cell that make up our bodies, and discuss how a series ofmutations can convert these well behaved cells into cancer cells, which grow,proliferate, and spread throughout the body precisely because they ignore thesestrict social rules. Finally we discuss the epidemiology of cancer and how it hasrevealed that there are mixture of environmental and genetic contributions tocancer.

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Cancer definitions

Tumor: a group of cells that has grown and proliferatedinappropriately

Benign tumor: confined to one part of the body, no migration

Cancer: malignant tumor

Malignant tumor: cells can escape, migrate, and settle at newlocations, and establish secondary tumors (metastasis)

Cell growth: increase in cell mass

Cell proliferation: increase in cell number

Before we can go further, we need to introduce some of the terms used todescribe cancer and the behavior of the cells that cause it. We begin bydefining what we mean by cell growth and proliferation. Many biologists usegrowth loosely to refer both to the increase in the size of individual cells andthe increase in the number of cells in a population that is due to cell division.We will use growth exclusively to refer to the increase in the mass of a cell andproliferation to refer to the increase in cell number, although, as we will seelater, most cells cannot proliferate for long without growing. Tumors aremasses of cells that have grown and divided where they shouldn’t have.Benign tumors are confined to one part of the body and because of this, mostcan be removed by surgery, giving a complete cure. Tumors becomemalignant when some of their cells escape from the original site, enablingthem to migrate to other sites in the body and establish secondary tumors,known as metastases. Once a tumor has metastasized, surgery cannot removeit, and many malignant tumors are resistant to chemotherapy and radiationtherapy. Strictly speaking, the term cancer is reserved for malignant tumors.

The last century has seen spectacular progress in our ability to prevent andcontrol infectious diseases, but we have made much less progress in defeatingcancer and it is still a disease that will kill one American in five. This year,40,000 US women will die of breast cancer.

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Committing to a man on the moon: May 25th,1961

Apollo 11 landing: July 20th 1969

Apollo program cost: $135 billion

One way of appreciating how hard a disease cancer has been to tackle is tocompare the pronouncements of two former Presidents. On May 25th, 1961John Kennedy declared that the United States should place a man on the moon,and $135 billion (in 2005 dollars) and 8 years, 1 month, and 29 days later NeilArmstrong stepped out of the Lunar Excursion Module. Since Richard Nixondeclared war on cancer on January 22nd 1971, the US has spent roughly $200billion on cancer research from federal funds, charitable donations, andresearch and development by pharmaceutical and biotech companies.

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Declaring war on cancer: Jan 22nd, 1971

Cost so far: > $200 billion

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Little progress on deadliest cancers

Leukemia: cancer with circulating white blood cells

Lymphoma: solid white blood cell tumor

34 years later, our success in this war mirrors that of our country’s adventure inIraq. Although victory has been declared, people are still dying. This slideshows what has happened since Nixon’s pronouncement by showing what howdeaths from two different cancers have changed in Britain over the last 25years. The blue line shows the number of men who die from Hodgkin’slymphoma. Lymphomas and leukemias are both cancer that affect cells ofthe immune system; in a leukemia, the cancerous immune cells circulate in theblood, whereas in a lymphoma, they are mostly found as solid masses in one ofthe organs of the immune system. The good news is that there has beendramatic progress in the therapies for Hodgkin’s lymphoma which has reducedthe number of deaths from these cancers by 75% and completely cured manypatients. The bad news is that this cancer is relatively rare and that we havemade far less progress on more common cancers. The red line on the graphdescribes deaths from colon cancer, which have fallen by less than 20%.Roughly 20 times more people are diagnosed with colon cancer than withHodgkin’s leading us to conclude that we are defeating some of the rarercancers but losing to the commoner ones.

The picture this slide paints is a general one. Although there has been dramaticprogress in cancer therapy it has mainly affected rarer cancers and for the bigkillers, lung, colon, breast, and prostate cancers, there has been little progress.

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Why can we send men to the moon and not cure cancer? At one level, theanswer is simple. Sending a spacecraft to the moon and bringing it back ispurely an engineering challenge, since the equations that govern the motion ofthe spacecraft are those of Newtonian physics. For cancer we need tounderstand what distinguishes cancer cells from normal ones and how onecancer differs from another before we can reliably kill all the cancer cells andspare the normal ones. As we will see, we have are only beginning toappreciate the full dimensions of our task, let alone devise strategies toaccomplish it. One of the most important realizations has been that cancer isnot a single disease, but a whole host of related disease, and that even cancersthat look identical to a pathologist can have different molecular defects.

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In the last few lectures, we will end up focusing on a particular form of cancer,chronic myelogenous leukemia, and a remarkable drug, Gleevec, that canspectacularly improve the health of patients suffering from CML.Unfortunately, like the single therapies for AIDS, Gleevec dramaticallyeliminates the effects of the disease but doesn’t cure it. When patients stoptaking the drug, their symptoms rapidly reappear, and even when they do keeptaking it, mutant cancer cells appear that are resistant to the drug. To tell thisstory, we will begin by worrying how cells can accurately replicate genomes aslarge as ours, talk about how our bodies’ cells cooperate with each other tosend our genes into the future, discuss simple observations that give importantclues about the nature of cancer, talk about the control of cell growth andproliferation (processes that are profoundly affected by cancer), discuss howcells receive and process the signals from their environment that controlgrowth and proliferation, and finish with a discussion of how Gleevec wasdiscovered, how it works, and how the evolution of the cancer cells eventuallymakes it fail.

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Germ Line & Soma

Multicellularity and the division of labor

Germ line mutations affect the next generation

Somatic mutations affect this generation

We begin our journey by pointing out that cancer arises because some cellsaccumulate mutations that alter their behavior in a way that eventually allowsthem to proliferate uncontrollably. Thus our bodies first defense against canceris to make as few mutations as possible, which means replicating their DNA asfaithfully as possible.

What are the consequences of mutations that occur in our cells? To frame thisquestion, we need to digress so that we can understand a fundamentaldistinction between two sorts of cells in our bodies, those that can give rise toour children and those that are destined to die with us. However proud we maybe of our own or our societies accomplishments, we exist for a brutally simpleevolutionary purpose, to project our genes as efficiently and as far into thefuture as possible. The projectiles in our bodies are our eggs and sperm, whichcan fuse with each other to give rise to new humans who will produce neweggs and sperm, and so on into what we hope will be the distant future.Collectively the eggs and sperm and the complete lineage of cells that connectthem back to the fertilized egg they developed from are called the germ line,because they contain the germ of the next generation of human beings. All thecells outside the germ line, form the soma (Greek for body) and are calledsomatic cells. They have a simple role and a finite future. They exist as asupport system for the germ line that helps the germ cells push their genes intothe future, and none of the somatic cells outlive us.

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Germ-line and Soma

This slide shows the distinction between germ line and soma in a well knownfamily. Queen Elizabeth’s egg and Prince Philip’s sperm came together toproduce the fertilized egg that would become the Prince of Wales. When thisembryo had reached a size of roughly 1000 cells, the few cells that were togive rise to the germ line could have been identified and it is the descendants ofthese cells that produced the sperm that fused with Princess Diana’s egg togive rise to Prince William. The rest of the cells in the embryo became thesoma of Prince Charles accounting for every part of him except the germ cellsthat give rise to his sperm and thus the line of succession in the Britishmonarchy.

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Germ-line and Soma

If, like Prince Charles, our bodies are mortal machines aiming to immortalizeour genes, why have our somatic cells accepted a supporting role in the moviethat will ultimately star your eggs or sperm? The answer is simple. The genesin your somatic and germ line cells are exactly identical. By helping your eggsand sperm escape into the next generation, your somatic cells are propagatingtheir own genes. Although there are a small minority of cells where thisstatement is not strictly true, the ability to produce animals like Dolly, wherethe nucleus of an egg was replaced with that from a somatic cell, demonstratesthat a sheep’s somatic cells have all the genes needed to produce a normalanimal. This experiment very strongly suggests that your somatic cells haveall the genes needed to produce a normal human and gives rise to the ethicaldilemmas about reproductive cloning. Thus although your somatic cells diewhen you do, their genes do not have to, because each time you make an eggor sperm, half of your genes enter a germ cell that can give rise to a child. Ishould make it as clear as possible that I am not describing a moral,philosophical, religious, or political position, simply explaining why the blindforces of evolution can accept the separation between germ line and soma.

Having explained the distinction between germ line and soma, we can return tothe discussion of mutations. Mutations in the germ line affect our descendants.If they are deleterious, they harm or kill them, if they are advantageous theyallow them to reproduce better. For mutations that cause cancer, they causecancer in our children if they occur in our germ lines and cancer in us if theyoccur in the soma;

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Germ-line and somatic mutations and cancer

Germ-line mutations can cause cancer in our children

Somatic mutations can cause cancer in us

Because mutations can either help or hurt, the mutation rate matters. If it is toohigh, enough embryos will die that the population falls in each succeedinggeneration, eventually extinguishing the species. If it is zero, no advantageousmutations occur, and evolution grinds to a halt.

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3 x 109 bp

3 x 109 bp(23 chromosomes) 3 x 109 bp

6 x 109 bp(46 chromosomes)

6 x 109 bp

All cells except eggs and sperm are diploid

25 cell divisions

What is the mutation rate in humans and what are its consequences? To makethings easy, we will assume that human cells are haploid, containing 23chromosomes and 3 x 109 base pairs of DNA. This is an accurate descriptionof an egg or sperm, but when they fuse with each other they make a singlediploid cell with 23 pairs of chromosomes and 6 x 109 base pairs of DNA,from which all of the cells that form your bodies have descended. But whenyou make your contribution to the next generation you pass on only half ofyour 46 chromosomes, half of your genes, and 3 billion base pairs of DNA.Thus for these simple calculations, we will worry only about the 3 billion basepairs of DNA that you might pass on to a child. We also need to take accountof how many cell divisions separate the egg that gave rise to our mothers fromthe one that produced the egg that we developed from. In the female germline, roughly 25 divisions separate the first division of a fertilized egg that willgo on to produce a woman from the division that produces the egg that thatwill give rise to her children.

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75*2.5 x 10-83 x 109Humanbeing

3*10-93 x 109Humancell

0.33 x 10-510000HIV

Mutations pergenome pergeneration

Mutations perbp per

generation

HaploidGenome

size

Mutation rates in HIV and woman

* Only 5% of these are in “useful” DNA

The best estimates suggest that when a human cell replicates its DNA, it makesa mistake about once for every billion base pairs of DNA it copies. Since eachcell must replicate about 3 billion base pairs of DNA, this suggests that aboutthree new mutations occur in each cell division . Thus roughly 25 * 3 = 75new mutations will appear in the cell lineage that connects the egg your motherarose from to the one that she produced to create you. Careful estimatessuggests that only 5% of the human genome is subject to natural selection,with the remainder being effectively junk, and leading us to conclude that eachnew egg contains 0.05* 75 ≈ 4 mutations that could be deleterious. Thesituation with sperm is slightly worse, since more cell divisions separate nextgeneration’s sperm from the fertilized egg that began this generation.

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75*2.5 x 10-83 x 109Humanbeing

3*10-93 x 109Humancell

0.33 x 10-510000HIV

Mutations pergenome pergeneration

Mutations perbp per

generation

HaploidGenome

size

Mutation rates in HIV and woman

* Only 5% of these are in “useful” DNA

We have now calculated how many new mutations we have inherited from ourparents with roughly 4 from our mothers and 6 from our fathers for a total of10 new mutations, of which we might expect something like half to bedeleterious. These mutations are unlikely to affect our health for the simplereason that most deleterious mutations are recessive to the wild type version ofthe same gene. This is a concept that many of you will have alreadyencountered, but for those who have not, a simple example comes fromconsidering human eye color. One of the genes that controls eye color exists intwo forms, which we will call blue and brown. The blue version (or allele togive it its technical name) is recessive to the brown version, or stated anotherway the brown version is dominant to the blue one. This means that if you geta blue copy from one parent and a brown copy from the other, your eyes willbe as brown as if you got two brown copies, one from each parent, and that theonly way you can end up with blue eyes is to get two blue copies, one fromeach parent.

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blue/BROWNblue/blue BROWN /BROWN

blue is recessive, BROWN is DOMINANT

Dominant and recessive forms of a gene

Because most deleterious mutations are recessive, they will only causeproblems if you get a mutant copy of the gene from each of your parents. Aslong as we are not European royalty or some other strongly inbred group, wehave children with people who are not closely related to us, and the chance ofboth sperm and egg harboring mutations in the same gene is small. For mostgenes, we can do perfectly well with one wild type and one mutant copy of thegene, allowing the human race to prosper despite what initially seems like afrighteningly high mutation rate.

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http://www.mcl.tulane.edu/classware/pathology/Krause/Blood/Neutrophil(k).JPG

Different cells, different life styles

Red blood cells

Life: 120 daysNumber: 2 x 1013

2,000,000 born/sec

Neuron(Purkinje cell)

Life: 100 years

Number: 2 x 107

Neutrophil


80,000 born/sec

Within the soma, mutations cannot be transmitted to our descendants, since oursomatic cells die with us. Thus you might hope that these mutations aren’timportant. For the vast majority of these mutations, this is true but we havealready mentioned that there is one important and tragic exception: cancerresults from mutations that remove the normal restraints over when and wherecells proliferate. Like mutation, cell proliferation is a double-edged sword; toolittle cell division means that new cells are born more slowly than old ones die,and we waste away; too much and a particular cell type tries to take over ourbodies.

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http://www.mcl.tulane.edu/classware/pathology/Krause/Blood/Neutrophil(k).JPG

Different cells, different life styles

Red blood cells


2,000,000 born/sec

Neuron(Purkinje cell)

Life: 100 years

Number: 2 x 107

Neutrophil


80,000 born/sec

We are made up of more than 100 different types of cells that perform differentfunctions and must be present in precise but flexible proportions to each other.Before talking about how these proportions are maintained it is worth makingthe different cell types concrete, and this slide shows three. Neutrophils areone of the types of white blood cells that track down and consume bacteria thatenter our bodies. We contain about 20 billion of these cells and they have anaverage lifespan of only three days, implying that your body is making 7billion new neutrophils a day and 80,000 new neutrophils a second. Your redblood cells, which carry oxygen from your lungs to your tissues live about 120days, and you contain a staggering 25 trillion of these cells, meaning that asyou listen to this lecture about 12 billion red blood cells will die and 12 billionnew ones will be made to replace them, an astonishing number when weremember the world’s current population is 6 billion. Finally, there are thenerve cells found in the part of your brain called the cerebellum that are calledPurkinje neurons. Each one of the 20 million Purkinje cells was born beforeyou were, contacts hundreds of other nerve cells, and lives as long as you do.

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Cancer: cell proliferation & behavior

Multiple changes in cell behavior cause cancer

Balancing cell birth and death

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Balancing death and proliferation

Cell birth rate = 1.01 x Cell death rate

Start 1 month(1.0131 = 1.36 x)

1 year(1.01365 = 38 x)

This introduction reveals that different cells in our bodies need to proliferate atvery different rates. Some, such as those that line our intestines, must bereplaced as often as once a day, whereas others like the neurons in our brainsrarely die or divide. To get from egg to embryo to infant to child to adultrequires precisely controlling where and when cells grow, divide, and die. Thesame is true for maintaining our adult form; for our bodies to keep workingwithout changing in size or shape, cells must grow and divide to produce newcells at exactly the same rate as cells die. This applies not just to the somaticcells taken as a whole, but to each particular type of somatic cell. For exampleif your red blood cells die faster than new ones are born, the concentration ofthese cells in your blood will fall and you will become anemic. If you are ahealthy person who takes erythropoietin, a protein that induces theproliferation of the precursors to red blood cells, the opposite is true and theconcentration of red cells will increase, improving your performance at sportsthat require endurance, but putting you at risk of being banned from competingin them.

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Balancing death and proliferation

Cell birth rate = 1.01 x Cell death rate

Start 1 month(1.0131 = 1.36 x)

1 year(1.01365 = 38 x)

It is worth trying to appreciate how precise this coordination must be. Some ofyou will have heard during your high school biology classes that if youflattened out the lining of your small intestine it would occupy the same area asa standard tennis court. The cells that cover this area are replaced roughlyonce day. If 1% more cells were born each day than the number of cells thatdied, the number of cells lining your intestine would go up by 1% a day. Overa month, the number of cells in lining your intestine would increase by 1.0131

corresponding to 1.36 fold. This seems mildly troubling but is nothingcompared to what happens over a year, since 1.01365 equals a 38 fold increasein the number of intestinal cells, which would imply that either the surface ofthe intestine or the thickness of its lining must have increased dramatically.This calculation shows that it would be almost impossible to achieve theprecise balance between the birth of new cells and the loss of old ones, if therates of the two processes are controlled independently. Instead supply mustbe matched to demand, implying that the body has ways of detecting that it hastoo few or too many of a particular cell type and then increasing or decreasingthe rate at which it produces new cells. Although we understand some of thefeatures of this market economy, for no cell type do we understand the precisedetails of how our bodies match cell birth and death rates to our needs. Intotality, your somatic cells are the perfect socialist state, with each contributingaccording to their ability and growing and proliferating in response to yourbodies needs.

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Evolving dogma: proteins come next - HUIT Sites Hostingsites.fas.harvard.edu/~lsci1a/11-28notes.pdf · Evolving dogma: proteins come next RNA Protein Energy harvesting Locomotion