Download Supplemental Figure Legends

Legend to Supplementary Figure 1
Hierarchical (unsupervised) clustering of differentially expressed genes in all individual
samples. This dendrogram was created using genes differentially expressed by at least
1.5-fold as a means to assay reproducibility. Samples highlighted in yellow are those
whose replicates cluster immediately next to each other, while those in pink cluster within
two dendrogram branches of one another.
Legend to Supplementary Figure 2
Frequency distribution of ‘Present’ calls for genes considered ‘Present’ in at least one IE
sample out of the 29 profiled. The vast majority (over two-third) of genes are ‘Present’ in
more than 90% of the samples, whereas less than 500 genes are ‘Present’ at other
frequencies.
Legend to Supplementary Figure 3
Heat maps of genes following all of the patterns described in Table 2 in the text (including
those shown as Figures 3A and 3B in the text) using genes differentially expressed by 2fold or more. Refer to Table 2 for a description of each pattern and to the legend to Figure
3 for a description of the heat maps.
A. Heat map of genes exhibiting the expression pattern E, M, and L (shown as Figure 3A
in text).
B. Heat map of genes exhibiting the expression pattern EM.
C. Heat map of genes exhibiting the expression patterns EL and ML.
D. Heat map of genes exhibiting the expression patterns Coch and V.
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E. Heat map of genes exhibiting the expression patterns Yng-M, Old-M, E10.5-Up, E10.5Down, E11-Up, and E11-Down.
F. Heat map of genes exhibiting the expression pattern Both-M.
G. Hear map of genes exhibiting the expression patterns C, U, S, CS, CU, and US (shown
as Figure 3B in text).
H. Heat map of genes exhibiting the expression pattern Yng-L, Old-L, E14-Up, and E14Down.
I. Heat map of genes exhibiting the expression pattern Both-L.
J. Heat map of genes with expression patterns IE-Up and IE-Down in at least one-third of
all IE samples.
Refer to Supplementary Table 4 for a listing of the individual genes and their fold-changes
from each expression pattern.
Legend to Supplementary Figure 4
A. Self-organizing maps (SOM) that group genes following the “Both-M” expression
pattern. Refer to Table 2 for a description of this pattern, and also Supplementary Figure
3F for a heat map of this pattern of expression. The y-axis is the relative expression level
of the genes in a given square (centroid). The order of the data-points on the x-axis going
from left to right is the same as that at the top of Supplementary Figure 3F (10.5C, 11C,
11.5C, 12C, 10.5V, 11V, 11.5V and 12V). The number in the top left corner of each
centroid refers to the centroid number. The number in the top center of each centroid is
the total number of probesets (note that there many be more than one probeset per gene
in this case) with that particular centroid pattern. The dark blue line traces the average
expression of all probesets within each centroid. The upper and lower red lines trace the
2
expression pattern based on maximal and minimal expression values for each data point,
respectively. Note that the maximal and minimal values, going left to right, are not
necessarily from the same probeset.
B. An SOM that groups genes following the Both-L pattern of expression (see Table 2).
The order of data points on the x-axis is the same as in Supplementary Figure 3I (12.5C,
13C, 13.5C, 14C, 14.5C, 15C, 12.5U, 13U, 13.5U, 14U, 14.5U, 15U, 12.5S, 13S, 13.5S,
14S, 14.5S, 15S). All other descriptions from 4A above also apply.
Refer to Supplementary Table 4 for a listing of the individual genes within each of the
centroids of these SOM’s.
Legend to Supplementary Figure 5
This is a ‘complete’ version of the data that is presented for seven pathways in Figure 4 of
the text. In this case all of the 53 significant biological pathways are shown. Otherwise,
the legend to Figure 4 in the text also applies.
Legend to Supplementary Figure 6
This is a higher resolution copy of Figure 2 in the text. It differs from Figure 2 in that it has
not been cut into different sets of centroids to highlight similar expression patterns.
Otherwise, the legend to text Figure 2 applies.
3
Legend to Supplementary Figure 7
High resolution copy of Figure 6A in the text showing the localization of Hey2 transcripts in
the cochleae at E14.5. The lower panel is an additional replicate for this organ.
Legend to Supplementary Figure 8
High resolution copy of Figure 6A in the text showing the localization of Hey2 transcripts in
the vestibular organs at E14.5. No significant expression is detected for this gene at this
stage. All abbreviations are as in Figure 1.
Legend to Supplementary Figure 9
High resolution copy of Figure 6B in the text showing the localization of FoxP1 transcripts
in the inner ear at stage E11.5
Abbreviations: Vest, rudimentary vestibular organ; Coch, rudimentary cochlea.
Legend to Supplementary Figure 10
High resolution copy of Figure 6B in the text showing the localization of FoxP1 transcripts
in the inner ear at stage E13. All abbreviations are as in Figure 1.
Legend to Supplementary Figure 11
High resolution copy of Figure 6B in the text showing the localization of FoxP1 transcripts
in the inner ear at stage E14.5. All abbreviations are as in Figure 1.
4
Legend to Supplementary Figure 12
High resolution copy of Figure 6C in the text showing the localization of Irx5 transcripts in
the cochlea at E14.5. All abbreviations are as in Figure 1.
Legend to Supplementary Figure 13
Higher magnification image of the cochlea labeled with antisense riboprobe in
Supplementary Figure 12 showing a stronger Irx5 expression in a stripe of cells at the very
outer edge of the cochlear curve. The expression in these particular cells, as in other
regions of the cochlea, also diminishes in a gradient from the base to the apex.
Legend to Supplementary Figure 14
High resolution images showing expression of Clusterin in the inner ear at stage E15 (the
lower panel in this figure is the same as the right panel of Figure 6D in the text). The
cochlear-specific signal is so intense that it easily be seen even before separating the
inner ear tissue from the developing temporal bone (upper panel). All abbreviations are as
in Figure 1.
Legend to Supplementary Figure 15
High resolution images showing expression of Clusterin in the inner ear at stage E15. The
upper panel shows tissue labeled with the control sense riboprobe, and is the same as the
left panel of Figure 6D in the text except that it was photographed under a different light
contrast setting on the microscope. The lower panel is an additional replicate using the
antisense riboprobe.
5
Legend to Supplementary Figure 16
Expression of Kcnd2, a Shal-related potassium voltage-gated channel, in the inner ear at
stage E14. The upper and lower panels show labeling with antisense and sense
riboprobes, respectively. Strong expression is observed in the vestibular organs, most
notably in the saccule and the utricle. In the latter organ, the transcripts of this gene
appear to be localized in a region where nerve fibers are found. This observation is
consistent with microarray results which also show a significant up-regulation of this gene
in the vestibular organ.
Legend to Supplementary Figure 17
Expression of Ttyh1, a homolog of the Drosophilla tweety gene which functions as a
calcium-independent, volume-sensitive large conductance chloride ion channel. The upper
and lower panels show labeling with antisense and sense riboprobes, respectively. Strong
expression is observed in the vestibular organs, most notably in the saccule and the
utricle. In the latter organ, the transcripts of this gene appear to be localized in a region
where nerve fibers are found. No expression is detected, however, in any of the three
ampullae. Note that the source of the signal at the tip of the posterior ampulla (PA) is most
likely residual mesenchymal tissue adhering to it, and not the ampulla itself. Faint
expression is also detected in the middle region of the cochlea (gray arrows). This is in
agreement with the microarray results as well as semi-quatitative RT-PCR results
(Supplementary Figure 22) in that the expression is significantly higher in the vestibular
organs than in the cochlea. It is especially interesting to note that the protein product of
this gene has been shown to be localized along the axons of neurons in primary rat
hippocampal cell cultures (MATTHEWS et al. 2007).
6
Legend to Supplementary Figure 18
Expression of Slc2a3, a facilitated glucose transporter, at stage E9. In the top panel, the
sense and antisense riboprobes were hybridized to embryos on the left and right,
respectively. White bracket indicates the otic cup which appears to be surrounded on its
immediate dorsal side by a population of cells with a stronger expression of this gene.
Legend to Supplementary Figure 19
Top-view of the embryo hybridized with the antisense riboprobe for Slc2a3 at stage E9.
Expression is detected in the head region, particularly in cells on the surface which are
most likely ectodermal/neural crest in origin. Of interest is the more intense signal detected
in cells adjacent to the dorsal side of the otic cup (denoted by white brackets). In the inset
are shown the otic cups by themselves after dissecting them from the embryo. The signal
appears to be localized along the dorsal rim of the cups. These results are in agreement
with both the microarray profile of this gene as well as with semi-quantitative RT-PCR
analysis (Supplementary Figure 22) which demonstrate highest expression in the otic cups
followed by the next highest expression in the surrounding non-inner ear tissue at this
stage.
Legend to Supplementary Figure 20
Slc2a3 RNA in-situ on embryos at stage E10 using the sense (left embryo) and antisense
(right embryo) riboprobes. No appreciable signal was detected at this stage, consistent
with microarray and also semi-quantitative RT-PCR (Supplementary Figure 22) results.
7
Legend to Supplementary Figure 21
Expression of Zbtb16, a zinc finger and BTB/POZ domain containing gene, at stage E9.
Consistent with microarray results, transcripts for this gene are detected both in the otic
cups and the surrounding non-inner ear tissue at this stage of development. Additionally,
the gene appears to be expressed throughout most of the anterior half of the embryo.
Legend to Supplementary Figure 22
Semi-quantitative RT-PCR for eight genes to validate microarray results. Total RNA from
all 32 samples used in this study (shown by labels above each lane) was reversetranscribed and used to amplify by PCR the genes indicated. Each gene was amplified in
the same reaction with Gapdh which was then used to normalize for variations in the
amount of template used. The graphs on the right are shown in order to compare the
profiles of the genes obtained after normalizing the intensities of Gapdh bands (graphs on
the left side) with profiles obtained by microarrays (graphs on the right side). Both
approaches were observed to delineate the same basic trend of expression. Refer to
Supplementary Table 9 for a comparison of the actual fold-changes using these two
approaches. Note that because agarose gel-based quantification is not particularly
sensitive, the fold-changes are much lower using this particular method when compared
with fold-changes from microarrays. Nevertheless, almost all changes are more than 1.5fold and they place the genes within the same patterns as do microarray fold-changes.
8
Legend to Supplementary Table 1
Summary list of 222 genes that, when mutated, cause inner ear defects in either humans
and/or model organisms. Human genes are shown in capital letters, and the symbol in
parentheses is for the human ortholog of the mouse gene. If the gene was found to be
differentially expressed within IE samples, column 4 indicates which patterns of expression
from the three analyses (EML, M, L) the gene follows, as well as the observed foldchanges in parentheses. If the gene’s expression was found to change based on both
developmental stage and tissue-type, the number(s) in parentheses refer(s) to the
centroid(s) in either Supplementary Figure 4A (if Both-M) or 4B (if Both-L). Because some
genes are represented by multiple probesets on the array, some genes may have two or
more centroid numbers separated by a vertical bar indicating which centroids the different
probesets for that gene fall into. Also indicated is whether the gene was found to be upand/or down-regulated in at least one IE sample relative to at least one NIE sample. The
actual IE and NIE sample(s) is/are indicated in columns 5 and 6 respectively, with vertical
bars separating the results from individual probesets. The gene list was compiled from
one or more of the following; Anagnostopoulos, (2002), http://www.jax.org/hmr/map.html,
http://www.sanger.ac.uk/PostGenomics/mousemutants/deaf/, http://webhost.ua.ac.be/hhh/,
and http://hearing.harvard.edu/db/genelist.htm. This table only includes data for genes that
were present on the gene chip used in this study.
Of the 222 genes, a total of 169 (76%) were present in either one IE or NIE sample.
Within IE tissues only, 160 (72%) were detected as being present in at least one sample,
and of these, 121 (76%) were differentially expressed by at least 1.5-fold (FDR <= 0.5%
and, where applicable, ANOVA p-value <= 0.005) in at least one of the three analysis
described. Also from the 160, a total of 66 (41%) were up-regulated in at least one IE
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sample compared to at least one NIE sample by at least 2-fold. Within NIE samples, 116
genes (52%) were detected as present and 16 (14%) of these were down-regulated in at
least one IE sample relative to at least one NIE sample by at least 2-fold.
Of the 160
genes present in at least one IE sample, 53 (33%) were absent in all NIE samples,
whereas only 9 (8%) of the 116 genes present in at least one NIE sample were absent in
all IE samples. Note that these numbers are not indicative of a true false negative rate
(FNR) in the data set. This is because some genes, even although they cause inner ear
defects when mutated, may not necessarily be expressed in the particular mouse IE or NIE
samples profiled in this study. For example, Slc26a5 (Prestin), which is the cochlear outer
hair cell motor protein, is not expressed appreciably until after birth when these cells
acquire electromotility (Belyantseva et al. 2000; He et al. 1994). Therefore, to obtain a fair
estimate of the FNR, only those genes that were absent in all IE and NIE samples used in
this study, but which have also been previously detected by RNA in-situs in at least one of
these time points or tissues, were considered. Specifically, of the 53 (out of 222) genes
scored as being absent in all of our samples, 16 have been shown by others to be
expressed in at least one of these tissues during this developmental period in the mouse
(Hes1, Jag1, Jag2, NeuroG1, Nog, Nr4a3, Pcdh15, Rara, Fgf3, Fgf8, Barhl1, Gsc in IE and
Rarg, Shh, Wnt1, Wnt3a in NIE tissues; references Zheng et al. 2000; Zine et al. 2001; Ma
et al. 2000; Lanford et al. 1999; Ponnio et al. 2002; Murcia and Woychik 2001; Romand et
al. 2002; Pirvola et al. 2000; Ladher et al. 2005; Li et al. 2002; Gaunt et al. 1993;
Riccomagno et al. 2002; Parr et al. 1993). In order to determine the FNR, we removed
from the 222-gene list the 37 genes absent in all of our samples and for which no in-situ
data were available during this period of mouse IE embryonic development, and expressed
the 16 genes mentioned as a fraction of the remaining number of genes.
10
Of the 53 deafness genes (shown in uppercase in Supplementary Table 1), 45 (85%) were
present in at least one sample from either IE or NIE tissues. Specifically, 24 were present
in at least one sample from both IE and NIE tissues, 18 only in at least one IE, and 3 only
in at least one NIE tissue. The expression patterns of these latter 3 deafness genes (Pax3,
Pou3f4, and Snai2) are consistent with previous observations that also demonstrate that
they are expressed in NIE tissues. For instance, Pou3f4 is expressed primarily in the
mesenchyme surrounding the inner ear (Phippard et al. 1999) whereas Pax3, which is
involved in the migration of neural crest cells and melanocytes, is strongly expressed in the
neural tissue surrounding the inner ear (Buckiova and Syka 2004). Moreover, Snai2, also
known as Slug, has been shown to be expressed in migratory neural crest cells (Jiang et
al. 1998). Of the 8 deafness genes that were absent in all samples (Pcdh15, Slc26a5,
Col4a3, Col4a4, KcnQ1, Ndph, Ush2a, and Tmc1), only 1 (Pcdh15) has been shown to be
expressed in the mouse inner ear by RNA in-situ (Murcia and Woychik 2001) in at least
one sample profiled in this study; therefore, this is the only verifiable false negative. The
expression of the other 7 deafness genes during this embryonic developmental period of
the mouse inner ear has either not been assessed or has not been detected by in-situs
(references Belyantseva et al. 2000; de Castro et al. 2006; Berger et al. 1996; Adato et al.
2005; Vreugde et al. 2002; Kurima et al. 2002).
11
Legend to Supplementary Table 2
Analysis of genes that are “Present” in various samples.
‘Numbers Summary’ indicates the actual number of genes considered ‘Present’ in each
of the 29 IE and 3 NIE samples, as well as the number of genes uniquely ‘Present’ either
in only IE or NIE samples.
‘Individual Genes’ lists all genes that were considered
‘Present’ in at least one sample, and indicates in which particular samples (IE and/or NIE)
the gene was ‘Present’ or ‘Absent’. See Supplementary Methods for a description of this
analysis.
Legend to Supplementary Table 3
Listing of significant molecular function (MF) gene ontology (GO) classes of genes
considered to be ‘Present’ transiently or ubiquitously. If genes were found in 20% or less
of all IE samples they are listed as “‘Transient”. Those ‘Present’ in 80% or more of all IE
samples are listed as “Ubiquitous”. The significance p-value is from Fisher’s exact test.
Also shown is the total number of genes belonging to a particular GO term from each list
(transient and ubiquitous) as well as the proportion of each list they represent. The
symbols for actual genes from each GO term are shown in the right-most column.
Legend to Supplementary Table 4
Gene lists for all expression patterns. ‘Patterns within IE’ lists all genes differentially
expressed within IE samples from the three analyses (EML, M, and L), their Entrez IDs,
fold-changes, and the actual pattern of expression (abbreviated according to the
nomenclature in Table 2 in the main text). ‘IE-Up and IE-Down’ lists all genes up- and
down-regulated in at least one IE sample relative to at least one NIE sample (IE-UP and
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IE-DOWN, respectively). Also indicated in the second column is whether or not a gene was
represented by multiple probesets on the gene chip. The third column shows the number
of IE samples in which the gene was either up- or down-regulated, and these are indicated
in the fourth column as a percentage of all 29 IE samples. Note that for genes with multiple
probesets, the median number of samples is shown. The fifth column lists the actual IE
samples where the gene was up- or down-regulated (with results from multiple probesets
separated by a vertical bar).
Legend to Supplementary Table 5
Significant MF GO classes unique for genes within each type of expression pattern.
Genes from each of the EML, Middle, and Late analyses are presented in separately
named tables. The individual genes within each GO term are indicated in the right-most
column, together with their fold-changes in parentheses. All GO classes shown have a
significance p-value of less than or equal to 0.05 from Fisher’s exact test, and contain at
least 2 genes differentially expressed by at least 2-fold. Note that genes following the
expression patterns Coch, C, and E14-Up did not represent any significant unique GO
terms, and hence are not shown here.
13
Legend to Supplementary Table 6
Listing of the 53 significant biological pathways and genes found within those pathways in
each of the 28 detected expression patterns. Four separate listings are presented
according to the four types of analyses: EML, Middle, Late, and IE-vs-NIE. Genes in bold
indicate the specific type of expression pattern where the pathway was found to be
statistically significant (Fisher’s right-tailed exact test p-value of 0.05 or less) with at least
two genes differentially expressed by more than 2-fold (EML analysis) or 1.5-fold (M and L
analyses).
Legend to Supplementary Table 7
Genes that exhibit dramatic up- or down-regulation in one specific tissue from one specific
developmental stage. The numbers in the column titled ‘Centroid’ refer to the centroid
numbers in text Figure 2 and Supplementary Figure 6. The ‘FDR’ column indicates the
false discovery rate calculated using Significant Analysis of Microarrays using the
multiclass option. ‘P’ and ‘A’ denote probesets whose expression was detected only in the
sample where their expression peaked or was not detected only in the sample where their
expression dipped, respectively.
Legend to Supplementary Table 8
Listing of mouse genes the orthologs of which fall within uncloned human non-syndromic
deafness intervals. This is a complete listing of the data selectively presented in Table 4 in
the main text.
The ‘Summary’ lists the 54 uncloned human non-syndromic deafness
intervals that contain at least one gene whose mouse ortholog was found to be ‘Present’ in
at least one IE sample profiled. Also shown are the chromosomal bands of these genomic
14
intervals, the markers defining their boundaries, their size, total genes within them, and the
proportion that were differentially expressed. ‘Genes’ lists mouse genes (columns D and E
in the excel file) the human orthologs of which (columns B and C) fall within uncloned nonsyndromic deafness intervals (column A). All genes shown were scored as being ‘Present’
in at least one of the 32 samples profiled in this study. Indicated are the proportions of
various samples in which these genes were scored as being ‘Present’ (columns F though
K). Also shown in column L are the actual patterns of differential expression that the gene
followed within IE samples (see Table 2 for a description of these patterns). A dash
indicates that the gene was not significantly differentially expressed based on the criteria
employed in this study (see Supplementary Methods). Columns M and N show the percent
of IE samples (29 total) in which a gene was up-regulated or down-regulated, respectively,
relative to the NIE samples. Note that some genes appear more than once because they
may be part of genomic intervals that are overlapping and/or very close to one another.
Legend to Supplementary Table 9
Eight genes whose expression patterns observed with microarrays were validated using
semi-quantitative RT-PCR (see Supplementary Figure 22). This table compares the foldchanges of the patterns obtained using the two methodologies. For the IE-Up pattern, the
number of samples with a 2-fold or more change is shown, and the actual samples are
also listed. For microarrays, the vertical bar separates the results obtained from different
probes for the gene.
15
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