Epistasis III

In many ways, the two different definitions of epistasis in the previous posts are a bit like blind men describing different parts of an elephant.  Statistical epistasis at the population genetic level can be caused by genes whose products directly interact, as in biochemical genetic epistasis, but it can also be cause by indirect interactions between gene products (i.e. one or more intervening molecules in a developmental or metabolic network).  Many traits, including human disease states, are affected by epistasis among multiple genes.  These types of higher order interactions are difficult to characterize and understand.
There are other complications.  From a population genetic standpoint, many compensatory epistatic situations, such as the parallel pathway example given in the previous post, many not "read" as epistasis statistically.  Genes can be viewed as adding pluses (+) and minuses (-) to an overall trait value, which can be obtained by adding up the sum of the + and - alleles. A mutation that turns a + into a - can be compensated for by a second mutation that changes a - to a +.  If their effects simply add to a sum, then this is not considered statistical epistasis, it is simply "additivity". Additive gene actions formed the original basis for the field of quantitative genetics, and such additive effects are still believed to provide the basis of most adaptive evolution and responses to artificial selection (as in agricultural and domestic animal and plant breeding).  However, quantitative genetic experiments have uncovered a great deal of statistical epistasis in the "genetic architecture" of trait differences between different strains of the same species and between different species.  It now appears that epistatic gene action is just as important as additive gene action in these architectures.  Understanding the molecular mechanisms underlying these gene interactions is a large task that still mostly lies ahead.

Epistasis II

Cell and developmental biologists have a different working definition of what epistasis is from what I described in the previous post.  In these fields, multigene pathways whose normal function is required for a particular phenotype are studied. Two genes show epistasis if the double mutant phenotype is either (a) the same or not much worse than either single mutant phenotype, (b) similar to or the same as wild type (a compensatory interaction), or (c) worse than the sum of the single mutant effects.
(a) can occur in a linear molecular pathway [e.g. compound a is converted by enzyme A to compound b, which is then converted by enzyme B to compound c, which is then converted by enzyme C to compound d].  In an individual with a mutation in the gene enconding enzyme B, there is not much production of compound d.  Likewise, an individual with a mutation in the gene encoding enzyme C also does not product much of the compound d.  In an individual with both mutations, there is again very little production of compound d.  Thus the presence of one of the mutants masks the effects of the other mutant in the same genetic background.  Biochemical methods that quantify the amounts of all of the compounds in the pathway (a,b,c, and d) can be used to identify which steps(genes) are effected in each mutant.  This type of biochemical genetic work in bacteria and fungi greatly helped to initially characterize most of the pathways of basic cellular metabolism in the middle part of the 20th century.

Two pathways may act in parallel, such that when one is knocked out by a mutation, the other is able to mostly or completely compensate.  In this situation, the first mutation may be nearly or completely undetectable, or it may cause only a modest decrease in the function of its pathway and hence a mildly deleterious phenotype.  The second mutation would knock out  the parallel "backup" pathway, resulting in a great or completely loss of the product of the two pathways, and hence a severe phenotype or lethality (a dead organism).  This is the basis of many "enhancer suppressor screens" in model organisms (predominantly Drosophila and Caenorhabditis in animals) that have been used with high effectiveness to characterize developmental and cellular signaling pathways.

The parallel pathway situation can also be the basis of compensatory epistasis..  If pathway 1 and pathway 2 both contribute to the production of compound A and a certain amount or concentration of A is needed (i.e. not too much and not too little), then a mutation that increases the production of compound A from pathway 1 can be compensated by a second mutation that decreases the production of A from pathway 2.  Of course, many parallel pathways likely have this type of compensatory action built into them.  A could act to inhibit gene expression or protein/enzyme activity in either or both of the pathway, such that an excess of A acts to turn down its own production until its level falls below a certain threshold.

Epistasis

Now for some science.  Epistasis, something my lab group has been interested in for a number of years, is interaction of alleles (the versions of genes that diploid individuals in sexually reproducing species have two of, one from each parent) such that the effects of two (or more) alleles do not equal the sum of the individual effects of each allele.  For example, at two gene loci a and b if there are wild type alleles (a+ and b+) that each contribute 1 unit to a phenotype and two mutant alleles a1 and b1 that each contribute 3 units by themselves (thus the diploid genotypes a+a1 b+b+ and a+a+ b+b1 both have values of 1+3+1+1=6), if there were no epistasis then the genotype a+a1 b+b1 would be expected to have a phenotypic value of 1+3+1+3=8.  However, it is often found in real biology that the effects of two mutant alleles (or two alternative wild type alleles) do not precisely add up to the sum of their individual effects, such that a+a1 b+b1 might have a genotype of 10 (synergistic epistasis) or 6 (masking epistasis; there are other terms for this that are escaping me at the moment).
If this seems complicated now, it gets a lot more complicated, especially when more than two loci are involved. Population genetics theory has been done on positive and negative epistasis for deleterious alleles.  Positive epistasis occurs when as deleterious mutations accumulate, they have their worst effects when there are few of them in a genotype, with decreasing magnitudes of effect as more are added (this resembles the masking case above).  Negative epistasis occurs when the effect of adding another deleterious mutation gets worse and worse as more are added (this resembles the synergistic case above).  There turns out to be little empirical evidence of the latter in nature (or at least when genetic experiments have looked for it).  However, in theory negative epistasis is required for sexual reproduction to evolve in an ancestrally asexual species (i.e. for sexual reproduction to confer an evolutionary advantage greater than its costs).  This latter point is something I read about today (Peck JR, Waxman D, Welch JJ. 2012 Hidden epistastic interactions can favour the evolution of sex and recombination. PLoS One 7:e48382) and am still trying to wrap my mind around.
In general, epistasis determines the effect of a mutation. This depends on the "genetic background" (the genotypes at all of the other loci in the genome). In a population, there is typically a near- infinite number of potential genetic backgrounds, and some very much smaller number of predominant types that are largely determined by the major genes that interact at the molecular level with the gene of interest (either at the DNA, RNA, or protein level).  This becomes very important when trying to find and decipher the effects of disease genes in humans.

Resolutions

New Years resolutions are interesting experiments in will power, although most of the ones I make are pretty trivial.  One of last year's (2012) was to not buy any shoes this year.  I was successful in that and am thinking about extending that for 2013 (although my main pair of sneakers is getting ragged on the inside).  One of the ones from 2011 was to stop putting sugar in my coffee.  That was successful and is now permanent.  I recently switched to decaf and am making some pretty good decaf espresso at home these days.  It is pretty good without cream.  So I'm thinking for 2013 to drop cream from my coffee.  Another one for 2013 is going to be to take more family pictures.  All of the stuff since 2010 has made this pretty hard.  But I'll try.

Fat Chance Hotel - Public Image Limited

Not sure I've blogged about this song before.  Great low tempo underneath-hook, with Lydon's nearly monotone looming over all.  The build from the verse to the chorus here is tremendous.  I also love the background dissolution into some kind of discussion and then the very end mandolin and echo.  A gem of a song.

We Close Our Eyes - Oingo Boingo

[link] Not an expert on their stuff but I really like this song.  The sweeping vocal chorus does it.  Basically a one hook song.  Seems to map somewhere between Style Council and General Public.

Another commercial I loved.

Lite Brite.  We never had this and I have never played with one.

Another classic 70s Christmas commercial

The Norelco Santa commercial.

Carol of the Bells

The Andre commercial from the 70s really helped solidify this song for me as a, essential Christmas song.

Running to You - the Cars

One of my favorite tracks off their vastly under-rated (popularly, although critics usually praise it) 1980 Panorama album.  I've always loved the Cars' abstract blend of keyboards and guitars.  They lyrics are never much but the guitar and keyboard figures and constructions are quite sophisticated.  The production is very well done as well.  Altogether I get a complete atmosphere from them about the ambivalent turn of the decade aesthetics.  A lot was going on and a lot of different sounds were being broadcast.  The Cars' sounds have aged very well since then.

Girlfriend is Better - Talking Heads

[link] Few did it better than the Talking Heads, in terms of original sounds, grooves, and deep commentary on things.  For many of us who perform rock on stage, when we think of the absolute maximum of what we can effect up there, it's this.

We Stand a Chance - Tom Petty and the Heartbreakers

[link] One of the many great songs on the 1982 Long After Dark album.  One of my favorite all time albums.  Great chord progression.  Terrific integration of guitars and keyboards, like a lot of their early stuff.

Chiquitita - ABBA

ABBA gets unfairly stuck with a cliche label.  Most people know "Dancing Queen" (a great but way overplayed song in its time and after) and not much else.  This song had huge airplay when it came out in 1979. There are few pop songs with more power. I love the harmonies and the old world, cabaret-like, feel of the song.  There are a lot of qualities in this song that never appeared again in anything heard in America.

Desperate But Not Serious - Adam Ant

[link] Despite all the flamboyance, Adam Ant was full of good musical ideas and had a very successful, if unconventional, pop instinct.  I love the brass in the intro and choruses here.  The chord progression is gothic, and as such seems part of the first wave of goth sounds into pop.

Christmas Wrapping - The Waitresses

[link] From 1981. A great modern holiday song. I love the sort of laconicness of the lead vocal (Patty Donahue), which may derive a bit from Debbie Harry.  The song and band are classified as "new wave", which was a pretty diverse phenomenon.  This song has brass and sax, which quite a few 80s acts featured. There weren't nearly as many rules than as the later decades.

Return of the Mack - Mark Morrison

From 1996. Another one that hit me at a certain time in a certain mindset.  Can't really explain it.  It is hooky.  Love the mid-tempo groove.

The 12 Days of Christmas - Bob and Doug McKenzie

Another fun take on this song. Got into these guys a bit late because I never stayed up late to watch SNL and SCTV like everybody else in high school did.  But the stuff is still pretty funny.

Going Down to Liverpool (live) - The Bangles

[link] Playing drums and singing lead vocal is hard. I did it a bit in the bands I played in in Madison. Debbi Peterson does an excellent job here. This is a great song. The video is a really nice example of the pure talent The Bangles had.

Find Another Fool - Quarterflash

From 1981. Always overshadowed by the aesthetically similar Pat Benatar, I've long appreciated Quarterflash.  The songs are simple, with hooky chord progressions.  Rindy Ross's voice goes to some good high places (and she plays a pretty good sax as well).  Takes me back...

Christmas song list

For today's Dept. holiday party.

1. The 12 Days of Christmas

2. Jingle Bells

3. Silent Night

4. Deck the Halls

5. Frosty the Snowman

6. Santa Claus is Coming to Town

7. Rudolf the Red-nosed Reindeer

8. Silver and Gold

9. Jolly Old Saint Nicholas

10. Up on the Rooftop

11. Good King Wenceslas

12. Silver Bells

13. We Wish You a Merry Christmas

14. Blue Christmas

15. Holly Jolly Christmas

16. I Saw Three Ships

17. God Rest Ye Merry Gentlemen

18. We Three Kings

19. I Saw Mommy Kissing Santa Claus

20. Let it Snow!

21. The Christmas Song (Chestnuts roasting...)

22. O Christmas Tree

23. Walking in a Winter Wonderland

24. White Christmas

25 What Child is This (Greensleeves)

26. I'll Be Home For Christmas

27. It's Beginning to Look a Lot Like Christmas

28. Here Comes Santa Claus

29. Here We Come A-Wassailing

30. Do You Hear What I Hear

31. Have Yourself a Merry Little Christmas

32. Feliz Navidad

33. Ding Dong Merrily on High

34. I Heard the Bells on Christmas Day

Blue Christmas - Elvis Presley

My version is pretty different. But his is interesting.  More like a jam in this video.

Crybaby - Utopia

Great rock song (from 1984).  Never really understood the tight, almost overwrought production, especially apparent in the vocal and drums tracks.

The 12 Days of Christmas - Allan Sherman

I've always loved this.  A funny slice of the 60s.  And I would love to find a statue of a woman with a clock where her stomach ought to be (the one in the video is kind of lame, although the video itself is pretty fun).

Outside - The Fixx

[link] A couple of my high school friends got me into the Fixx and it stuck with me.  This song is one of their more obscure earlier songs.  Long and atmospheric.  (the only thing sort of strange about this live video is how the drummer is sort of over the top getting into this rather slow and cerebral song)
I used to take naps listening to tapes in those days and the Fixx were very frequent in my playlist.  There is a point where one starts to wake up from a nap and has sort of an altered consciousness.  This is one of the songs that would typically be playing during those moments.  Another Fixx song that tended to occur then was the song Camphor.

Stardom in Acton - Pete Townshend

From 1983.  This song was played a lot on rock radio.  Warmed up to it pretty quickly and I've always enjoyed it since then.  Complex dynamics, behind a pretty simple chord structure.

Yule Log

I remember this on WPIX from my youth.  We never watched it because we always had other sources of music.  I guess people did and now it's a kitchy nostalgic thing.  And of course it's on Youtube like everything else.  It's also a really safe outlet for viewers who are pyros.

Just Another Night - Mick Jagger

[link]  I've always liked this song, and actually most of Jagger's first solo album in 1985.  Great hooky chord progression.  Really that's all there is to it. Probably also hit me at a really formative time.

Christmas songs groupings

I've always mentally formed the following groups of songs:

Up On the Rooftop, Jolly Old Saint Nicholas

Jingle Bells, Sleigh Ride

Winter Wonderland, Let it Snow

I Saw Three Ships, I Heard the Bells on Christmas Day

There are more.  And higher level nesting.  I'll continuing putting this together...

Another Christmas music thing I have

The Nutcracker. Especially Dance of the Sugar Plum Fairies. Completely atmospheric. This music is winter for me. Probably just early conditioning, but still...

Snow, Snow! Beautiful Snow!

A lot could be written on this topic. This song is a pretty obscure song sung by school choruses in the early 80s (and I don't know how much longer before that).  I wasn't in the chorus in high school but my older brother Tom was and I remember seeing this song sung by them at least a couple of times.  It made a huge impression.  It became part of that feeling that I described in the last post.  So I have a lot of nostaligia for this piece.
The lyrics can be found here.  I can't find a date or author on this song.

As you can tell

I have a thing for Christmas songs.  I grew up with Christmas music.  When I was a kid there was a real "Christmas Feeling" I used to feel when hearing a lot of these songs (certain versions, certain records my parents had, e.g. Fred Waring holiday records).  It was mixed in with the excitement of getting gifts, but I like to think it was a distinct, special kind of feeling.  I don't feel it so much any more when the holidays come around, but I still really really enjoy playing the music of the holiday season.

New Christmas Learns

Feliz Navidad
Ding Dong Merrily on High
Have Yourself a Merry Little Christmas
I Heard the Bells on Christmas Day
Do You Year What I Hear?
Here We Come A-Wassailing
I Saw Mommy Kissing Santa Claus
It's Beginning to Look a Lot Like Christmas
Here Comes Santa Claus
God Rest Ye Merry Gentlemen
Let it Snow