#266 - AMA #50： Genetics： how they impact disease risk, what you can do about it, testing, and more
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Summary
In today's episode of the Ask Me Anything (AMA) podcast, we focus heavily on genetics. In this episode, we cover a variety of questions that you submitted over the past couple of years about genetics, genetic risk factors for various diseases, genetic testing, and the best options for genetic testing.
Transcript
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hey everyone welcome to a sneak peek ask me anything or ama episode of the drive podcast
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i'm your host peter atia at the end of this short episode i'll explain how you can access
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the ama episodes in full along with a ton of other membership benefits we've created
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or you can learn more now by going to peter atia md.com forward slash subscribe so without further
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delay here's today's sneak peek of the ask me anything episode welcome to ask me anything
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episode number 50 in today's episode we focus heavily on genetics if you've listened to previous
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episodes you've heard us touch on genetics in terms of a few genetic risk factors for various
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diseases most notably the apo e4 gene in alzheimer's disease however we really haven't spent time
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discussing how exactly genetics relate to disease more broadly and why it's so valuable to know these
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risks in today's ama we've gathered a lot of questions that you've poured in over the past
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couple of years and we cover a variety of items we cover some fundamental background on genetics
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reasons for getting genetic testing when it is useful when it is not and what types of tests are
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available what the testing logistics are and how to interpret the results all of this will help give
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us a foundation for when we talk about commercial direct-to-consumer genetic tests and considering
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when they're useful as well as which ones stand out and what the best options are for anyone looking to
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learn about their health i think this is really an important discussion around a topic that we see a lot
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of people talk about we see a lot of questions about but truthfully there are some fundamental things
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that i think are not necessarily understood by the public and i tend to think that people overweight
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the importance of genetic testing i've certainly been vocal about that but i want to call out areas
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where i think genetic testing can be valuable and i hope that this ama really lays that foundation
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so that you can become a more valuable consumer of genetic tests finally i think this will provide
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a great foundation for any upcoming discussions we have on the topics of genetics and i know that we have
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at least one really interesting one in the pipeline so if you're a subscriber and you want to watch the
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full video of this podcast you can find it on our show notes page if you're not a subscriber you can
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watch the sneak peek of the video on our youtube page so without further delay i hope you enjoy ama number 50
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peter welcome to another ama how you doing doing well how about you i'm doing good how's the day so far
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it's going okay well we'll get right into this one i think it should be a good one mainly because
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it's really on a subject that we get a lot of questions on but we haven't talked about this heavily
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in detail i was actually looking back and some of this was covered a very small section in ama number
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eight so way way back in the day with you and bob but for people who have listened to the podcast
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they'll have heard us touch on genetics but often in terms of how genetic risk factors for disease
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so the most notable example of what we've talked about is apo e and the apo e4 and alzheimer's disease
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but we've never really spent a lot of time discussing how exactly genetics relate to disease
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haven't really talked about why it's so valuable to know these risks and we get a ton of questions on
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these mainly from people who are saying hey i can do this direct-to-consumer test i can do this
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direct-to-consumer test are they valuable what do they tell me what do they not tell me and so
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compiled all those questions and we're going to really focus today just to understanding at a
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basic level genetics reasons for genetic testing types of tests available how to interpret results
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which will really frame the conversation on when thinking about commercial direct-to-consumer dna tests
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where are they useful where are they not how should someone think about them so i think anyone who
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listens to the podcast is going to find value in this topic it's a topic we really haven't covered
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in detail ever before so i think it's going to be really good and hopefully really interesting for a lot
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of people so with all of that said anything you want to say before we get started no i don't think so
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let's get into it all right so i think it'll be helpful to just kind of talk about the term genetics
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it's thrown around a lot when you hear people talk about inheriting certain traits or having risk factors
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and people kind of ask what are we really talking about when we refer to quote-unquote genetics and why is it
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even important yeah so i mean look when you know you hear people talk about nature versus nurture well this is
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what we mean by the nature part of it so when we're talking about genetics we're talking about the part of a
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person that has been passed down from the parents of course we differentiate this from the stuff that we talk about
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that's nurture related these are non-genetic traits that could be passed down by the way cultural
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socioeconomic traits etc genetics obviously play a very important role in understanding physical
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psychological social factors but what we really want to talk today are about these genetic pieces
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genetics can't be chained shy of genetic engineering which maybe we can talk about gene therapy and things
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like that but for the most part what we're thinking about is understanding how genes shape and
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predispose us to various conditions how perhaps having certain genetic conditions might make us
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choose certain lifestyle modifications as a result of that to modify risk and for example there are some
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genes that are completely deterministic we'll talk about what that means so there are certain genes
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where if you have the gene it's going to produce a trait regardless and there are many more genes for
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which if you have a certain gene you might not necessarily get the trait so anyway we hope to make sense of all of
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those topics today because i do think this is not a particularly well understood field once you get
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beyond the surface level i agree and i think the next question we received which i think makes a lot
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of sense at least from a like a non-science background of myself a lot of times when you think of genes i
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don't know why maybe it's just me you think of dna as well and so maybe just give us a quick rundown on
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what dna is how it works really in the sense of how it can impact our biology and traits dna is just
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a code of instructions that tell a cell how to function so there are lots of analogies here but
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i really think that the best one is kind of thinking of it as a cookbook so a cookbook will have you know
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discrete sets of instructions in the form of individual recipes and dna also has a discrete set of
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instructions in the form of individual genes you know a recipe is just a recipe right for it to
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become a meal someone needs to do something about it someone needs to read it and then follow it and
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actually do the cooking and genes are sort of the same way so they only work by being expressed so when
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you hear gene expression that's what we're really talking about so expression means making a copy of
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that dna into something called rna that process is called transcription and then turning that rna
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into a protein and that process is called translation and again you know if you think about it like
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proteins are more than just muscles right proteins are enzymes and other cofactors and things of that
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nature so you know basically everything that needs to get carried out in a cell is being done via this
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process i think one of the biggest surprises of the genetic revolution was the relative small number
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of genes that humans have and maybe for folks who aren't even familiar with this subject matter i think
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this is kind of a startling stat which is that humans only have about 20 000 protein coding genes in
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total maybe that sounds like a lot but if you consider the fact that lab mice on average have about
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23 25 000 genes krill these tiny sea plants whatever we're talking about like 29 000 genes rice mushrooms
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maybe 50 000 genes so when you think about things that are far simpler than we are and they have far
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more protein coding genes you realize that that's just part of the story and again i think one of the
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things that this now illustrates is that it had been long assumed that one gene led to one function
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and we now know that this isn't the case so a single gene can often be read in many different ways
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giving rise to many different strands of rna and by extension proteins which can then be modified
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post-translation to create even greater functional heterogeneity another question we got which fits really
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well right here is how are genetics passed down from a parent to child you know when we talked
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in the past about the apo e4 you get two copies and for someone to have a four you know one of their parents
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must have a four as well but maybe we should walk through how genetics are just passed down in general
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there's actually a really nice figure here that we'll use to make this a little easier to understand so nick
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if you don't mind pulling this up for those watching this i think this is an easier way to see it if
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you're not watching this and you're only listening i'll do my best to also explain this the figure will
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also be in the show notes of course okay so let's start from the simplest and go to the more complex
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so we're going to go all the way from a base pair to a chromosome so there are four base pairs in dna
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they're called nucleotides they're abbreviated by their letters g c a and t but just so we can say them
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once it's guanine cytosine adenine and thymine the g's and the c's can only be paired together the a's
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and the t's paired together so in other words if you know what one strand is you automatically know
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the other because each nucleotide can only be paired with one other nucleotide and that has to do
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with the way that they fit and the type of hydrogen bonds across them so the string of nucleotides
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is the genetic sequence and a certain number of them create a gene so a certain number of nucleotides
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strung out and it's usually thousands of them to be clear make up a gene so as you see looking at this
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figure you have like a long string of nucleotides and remember the whole thing with dna is that it
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creates that helix it's a double helix and that lengthy string of dna are divided into segments known as
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genes now these long strands of dna as genes wrap around other proteins called histones and those
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histones further organize and wrap up around really really large things that you can actually see under
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a microscope called chromosomes now humans have 23 pairs of chromosomes so for each pair what that means is
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we get one chromosome from the mother one chromosome from the father and the only thing that is a bit
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wonky here of course is that there are two of those that are sex specific so we have 22 pairs
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that would look identical from a mother or father and then you have your sex chromosomes which if you are
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in most cases phenotypically female you would have an x and an x if you are phenotypically male you would
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have an x and a y there are very rare exceptions to this rule so if you have an x x y you're sort of
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phenotypically male but you have these other characteristics so that's called klinefelter
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syndrome if you're x and no y i think that's turner's syndrome which is sort of phenotypically
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female but has different characteristics so again just for the most part it's going to be 22 pairs
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plus an x x or an x y what that means by the way is you're getting basically two sets of every gene
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those two copies could be identical or they could be different and the different versions are referred
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to as alleles so some traits result from a combination of the effect of both copies so hair
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texture is an example of that but other traits tend to follow a dominance pattern so one allele so
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meaning one of the parents alleles tends to be dominant so hair color for example so brown is
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dominant over blonde red you know all things considered equal if somebody with black hair
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somebody with blonde hair have a kid there's a more likely chance that that child is going to have
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darker hair for most genes like you know roughly 90 of the time having one functional copy is typically
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enough to produce a normal phenotype that image is really helpful to kind of paint the picture a little
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bit more of how this works and so you know the next question we received is how much do genes vary
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across individuals this is where it starts to get a little complicated right so everyone has the same
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set of genes but different individuals have small variations in the sequence of those genes or
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in the surrounding dna these are called snips or single nucleotide polymorphisms and these influence
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the genes level of expression or even the level of function of the genes protein product so just to
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put this in perspective think about how distinct you and i are genetically right like you probably
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descend from vikings in northern europe i clearly descend from people in the middle of africa we are
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still 99.5 percent or greater genetically identical in fact all humans are at least 99.5 percent
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genetically identical to each other again pretty remarkable that snips are only present in less
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than 0.5 percent of all base pairs for the entire human genome and yet that small small variation
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accounts for all the genetically attributable differences in variability across humans in height
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hair skin color susceptibility to diseases everything like you name it all the things about us that are
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genetically different are contained within less than 0.5 percent of our genome just to put this in
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perspective we share 99 percent of our dna with chimpanzees we share about 90 percent of it with cats
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you know like a pet cat perhaps my favorite statistic of all when getting you know prepared to talk about
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this that i didn't know was we're about 50 to 60 percent genetically identical to bananas and basically any other
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plant for that matter is that bananas with nubbins or without nubbins it depends so i have a unique
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snip that makes me much closer homology to those without nubbins i'm only like four percent related
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to bananas with nubbins which makes sense on why they're so dangerous to you absolutely yeah so genetic
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variation is not necessarily a bad thing of course when you do have genetic variation for humans it can
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exist on a spectrum so there are certain changes that can be completely benign likely benign many of
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them are unknown significance so people who are used to going through their own genetic material using
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third-party applications like prometheus what you'll notice is they have a lot of things that exist in
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the unknown significance right so we think of it as benign likely benign unknown possibly pathogenic and
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pathogenic and the reason for this is that a number of changes don't really affect the way dna is read
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and transcribed into rna and protein so remember dna purpose of this is to create the template that gets
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transcribed into rna rna gets translated into protein so our head of research katherine bergenbach came
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out with i think just a fantastic analogy here using the cookbook metaphor so imagine you have a recipe and it
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calls for two eggs so it's two space e g g s and there's a typo somewhere in the process of re
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translating that book it gets turned from two space e g g s into two space e g s s okay is the person who
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looks at that cookbook gonna know what to do yeah they will so there is a mutation there there's a
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polymorphism but it doesn't change the overall food product doesn't change the translation but what if
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the typo instead was changed from two e g g s to five e g g s so it went from two eggs to five eggs
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that's a material change and that's likely going to result in pathology so i loved that example that
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she came up with because it really illustrates why there are a lot of different ways you can
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re translate to space e g g s you could get rid of the space you could get rid of one of the g's
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there's a lot of ways you could do that and you'd still get the right answer but there's a lot of ways
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you can screw that up and so i think the last question in this kind of foundational section
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came from someone who said you know which traits are determined by genetics versus
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experience or environmental factors the degree to which a given trait or you know a health
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characteristic is determined by genetics is known as the heritability of a trait heritability describes
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the amount of phenotypic variation in a given trait in a population that can be attributed to the
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genetic variation in that trait so most traits are influenced by a combination of genetics environment
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experience and through a number of influencer factors so let's just kind of go through some of
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these right so some traits are entirely determined by genetics your blood type your eye color these are
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a hundred percent heritable others are basically completely determined by your environment and
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your experiences so your native language your religion so that would be the other end of the
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spectrum those are zero percent heritable but most things that we talk about fall somewhere in the
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middle and therefore genes and the environment and experience interact to determine many outward
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characteristics of appearance and personality and susceptibility to disease but not all so let's talk about the
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things that people tend to care about so height height is about 80 percent heritable so that means it's
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mostly determined by genetics but a lot of factors i.e. 20 percent of that can be determined by things such as
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childhood and gestational nutrition hazardous exposures like if the mom was smoking during pregnancy
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those can contribute to the other 20 percent this is kind of best studied you know looking at basically
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mono and dizygotic twins so peter maybe just for people who aren't sure the difference do you want to just define
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those two terms real quick too yeah sorry for the jargon so monozygotic twins are identical twins
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and what that means is that one egg and sperm were fertilized and then split into two identical
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meaning two identical genetic differences so monozygotic twins are identical twins and that arises when an egg and
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a sperm are fertilized and after fertilization they split so then you get two new cell growths that
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ultimately each become a fetus but they're genetically identical the dizygotic twins are when two eggs two
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different eggs are either inserted via ivf or ovulated through natural conception and then obviously
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they're fertilized with two different sperms so dizygotic twins are effectively siblings just normal
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siblings that happen to be born or carried at the same time so the difference between those genetically
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again at the macro level is pretty small because remember we talked about how you know we're all pretty
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similar and of course here you have non-identical versus identical siblings so the study of dizygotic
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versus monozygotic twins is a really interesting way to study certain diseases for example consider
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schizophrenia or autism when you look at the occurrence of schizophrenia or autism in monozygotic twins
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versus dizygotic twins what are you controlling for so in the monozygotic you're able to look at what happens
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in the same genes in the same in utero experience in dizygotic you have different genes same in utero
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experience and then you also have other experiments where you have monozygotic twins raised apart
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so same genes same in utero experience different environmental triggers these types of studies are
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what allow us to understand how heritable certain traits are and it's doing studies like this that we
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see that there is you know reasonable concordance for schizophrenia and even more concordance for
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autism so for example looking in the particular case of schizophrenia i believe that the studies
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have shown about a seven percent concordance between dizygotic twins while a 33 percent concordance in
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monozygotic twins which suggests about a 79 80 percent heritability for the condition so this is kind of more
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real world stuff where it's not black and white and it's not entirely heritable and it's not completely
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environmental i feel we've talked a lot about in podcast or you have with guests you often bring up you know have you
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studied this in twins it seems like it's a very popular thing across nutrition exercise whatever it may be do
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researchers just always try and seek out twins if you're a twin do you just have the ability to be in many more
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research studies how does that actually work yeah i mean certain studies especially studies that are
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trying to really understand mechanism of action to be able to have twins is a very powerful tool i mean
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to put it in perspective nick think about how much animal research is done in effectively twins i mean
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most animal studies are done in the equivalent of identical twin mice because they're just genetically
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bred to be identical you know they're monozygotic at all loci throughout their entire genome you might
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be doing an experiment on 300 mice but they're all exactly the same so there is great advantage to that
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of course there's a disadvantage to that as you move further down the study from efficacy to
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effectiveness at some point you want to know what works for everybody but everything has its time and
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its place and clearly there are certain things where studying identical twins is valuable yeah super
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interesting i think that kind of wraps the foundational section so we'll move to this next section which is
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just looking at genetic tests the different types uses limitations and more detail so i think the first
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question that makes sense to start here is just what are some of the reasons for someone to even get
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genetic testing done thank you for listening to today's sneak peek ama episode of the drive if you're
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